KYZATREX has generated strong results in both safety and efficacy studies for KYZATREX for treatment of primary and secondary hypogonadism in men. Due to the robust results, especially regarding safety, Marius has requested a Priority Review that, if granted, would result in an anticipated six-month review period.

Submission of our first NDA is an important milestone, which is the culmination of over a decade of meticulous research and dedication and is just the beginning for Marius, as our pipeline will continue to advance research and development in this important therapeutic area that has a multitude of effects on our health system, said Himanshu H. Shah, Founder and Executive Chairman of Marius.

The NDA submission is based on efficacy and safety data from its pivotal study (NCT04467697) in which KYZATREX generated the most comprehensive ABPM data in its class. KYZATREX was well tolerated by participants, with greater than 96% of those subjects completing 90 days of treatment achieving average testosterone levels in the normal range in the pivotal Phase 3 study. The most common treatment-related treatment-emergent adverse event (TEAE) in the pooled Phase 3 studies was hypertension, while there were no serious TEAEs across the Phase 3 trials deemed related to the study drug.

We are extremely proud to have generated compelling efficacy and safety data in our Phase 3 trials, commented Dr. Om Dhingra, Co-Founder and CEO of Marius. We look forward to continuing to work collaboratively with the FDA on the review of our application, and if approved, KYZATREX has the potential to become the standard of care (SOC) for the treatment of primary and secondary hypogonadism globally.

Marius also intends to file a marketing authorization application (MAA) with the European Medicines Agency in the first half of 2022. For more information about Marius Pharmaceuticals and KYZATREX, visit mariuspharma.com.

About Testosterone & Hypogonadism

Hypogonadism, often referred to as testosterone deficiency, is a condition that occurs when the body does not produce adequate levels of testosterone. In addition to testosterones widely accepted role in sexual and reproductive function, it also has important roles in numerous other metabolic and inflammatory processes. In the U.S. there are at least six million symptomatic men suffering from hypogonadism, and over 100 million men globally. The resulting medical costs associated with men with untreated hypogonadism and related comorbidities are more than $25 billion in the U.S. alone.

Hypogonadism is also the most common cause of secondary osteoporosis in men. Beyond these diseases, hypogonadism is a common comorbidity in a broader set of conditions from Type-2 diabetes to Non-Alcoholic Steatohepatitis (NASH).

About KYZATREX

KYZATREX if approved, will represent a novel oral testosterone replacement therapy option for adult males indicated for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired).

The ReTUNE study was a multi-center, 12-month study across the U.S. that studied the safety and efficacy of KYZATREX in hypogonadal subjects (total testosterone 281 ng/dL). Efficacy was determined by number of subjects in the normal, eugonadal range after 90 days of treatment, including dose titrations, while safety was monitored for a further 9 months while on a steady dose. In addition to testosterone parameters, the study collected Patient Reported Outcomes (PROs), which showed statistically significant results both from baseline and against its comparator. A pivotal six-month Phase 3 study was conducted, in which subjects were monitored using ABPM, now considered the standard BP assessment by the FDA and clinical experts. An improved dose regimen was also used in the pivotal six-month Phase 3 study. The results of the Phase 3 studies will be published in leading medical journals and presented at national conferences during 2021.

The FDA has conditionally accepted KYZATREX as the trade name for this investigational drug. The safety and efficacy have not been fully evaluated by any regulatory authority.

About Marius Pharmaceuticals

Marius is a specialty pharmaceutical company focusing on treating conditions that are primarily associated with hypogonadism, commonly referred to as testosterone deficiency. The companys mission is to improve the functional lives of patients and reduce the risks of the downstream effects of endocrine imbalance by ensuring appropriate level of testosterone. For more information, please visit http://www.mariuspharma.com .

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Whats more, unlike nuclear DNA, mitochondrial DNA passes virtually unchanged from mother to child, with a predictable rate of mutation that gave Dr. Sykes and other researchers a way to draw links between modern populations and ancient ones.

After the success of The Seven Daughters of Eve, which allowed him to buy a second home in Edinburgh and a blue Mercedes convertible with the license plate D7 EVE, Dr. Sykes set aside most of his academic work in favor of a career popularizing genetics through TV programs and general-interest books at a time when phrases like DNA sequencing were not yet household words.

He demonstrated an almost preternatural sense for distilling complex science through narratives and high-profile stunts, like Bigfoot Files, a three-part series that ran on British TV in 2013 in which he assessed claims about some three dozen hair and skin samples sent to him by cryptozoologists, people on the hunt for legendary creatures like the Loch Ness Monster and the Abominable Snowman.

While his results were definitive and not in their favor, his conclusion was magnanimous. Rather than persisting in the view that they have been rejected by science, advocates in the cryptozoology community have more work to do, he wrote in a paper announcing his results. It was an encouraging statement that won him legions of fans among a section of the public that is often at odds with the scientific establishment.

Bryan always wanted to be a gentleman scientist, said Sue Foden, his first wife, in an interview. He wanted science to be fun, and for people to enjoy.

Bryan Clifford Sykes was born on Sept. 9, 1947, in Eltham, a suburb of London. His father, Frank Sykes, was an accountant. His mother, Irene (Clifford) Sykes, was a homemaker. He studied biochemistry at the University of Liverpool, received his Ph.D. from the University of Bristol and arrived at Oxford in 1973 to pursue a doctorate in science.

Dr. Sykes married Ms. Foden in 1978. They divorced in 1984 but remained close, and had a son, Richard, together in 1991. A second marriage, to Janis Wilson, also ended in divorce. Along with his son, he is survived by his brother, Nigel Sykes.

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A breakthrough study published in Nature Genetics asserts identical twins also called monozygotic twins that develop from one fertilized egg may not be genetically identical, after all. The finding challenges the assumption scientists hold dear when studying the effects of nature versus nurture, particularly when looking at the impact of diseases: that twins have minimal genetic differences, so any difference in their experience of a bodily phenomenon stems from environmental factors.

So if you take identical twins raised apart and one of them developed autism, the classic interpretation has been that that is caused by the environment. But that is an extraordinarily dangerous conclusion, the co-author of the paper and head of Icelands deCode genetics, Kari Stefansson, tells The Guardian.

The new research suggests that identical twins had, on average, 5.2 genetic mutational differences between them. It also found 15% of monozygotic twins had an even higher number, beginning early in their development. This means some identical twins, right from their conception, have different DNA, which may affect how they experience diseases. Experts have welcomed this research, saying it upends the classical twin research model medical scientists use in determining the effect of biology versus environment on individuals experience of illness.

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The research may also change how we understand and refer to the phenomenon of twinning it may be more accurate to refer to such twins as monozygotic, instead of identical, Stefansson adds. The current research is one of a handful that challenges the identical-twins-are-identical assumption, but researchers note more investigation is needed to pinpoint the exact mutations (and when they occur) if the scientific community is to change how it studies disease.

For now, we know monozygotic twins are not identical but how, why, where, and when needs more digging.

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Identical Twins Are More Genetically Different Than We Thought: Study - The Swaddle

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Researchers have successfully used a DNA-editing technique to extend the lifespan of mice with the genetic variation associated with progeria, a rare genetic disease that causes extreme premature aging in children and can significantly shorten their life expectancy. The study was published in the journal Nature, and was a collaboration between the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; Broad Institute of Harvard and MIT, Boston; and the Vanderbilt University Medical Center, Nashville, Tennessee.

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Base editing for progeria treatmentProgeria is caused by a mutation in the nuclear lamin Agene in which one DNA base C is changed to a T. Researchers used the base editing method, which substitutes a single DNA letter for another without damaging the DNA, to reverse that change. Credit: Ernesto Del Aguila, NHGRI.

DNA is made up of four chemical bases A, C, G and T. Progeria, which is also known as Hutchinson-Gilford progeria syndrome, is caused by a mutation in the nuclear lamin A(LMNA) gene in which one DNA base C is changed to a T. This change increases the production of the toxic protein progerin, which causes the rapid aging process.

Approximately 1 in 4 million children are diagnosed with progeria within the first two years of birth, and virtually all of these children develop health issues in childhood and adolescence that are normally associated with old age, including cardiovascular disease (heart attacks and strokes), hair loss, skeletal problems, subcutaneous fat loss and hardened skin.

For this study, researchers used a breakthrough DNA-editing technique called base editing, which substitutes a single DNA letter for another without damaging the DNA, to study how changing this mutation might affect progeria-like symptoms in mice.

"The toll of this devastating illness on affected children and their families cannot be overstated," said Francis S. Collins, M.D., Ph.D., a senior investigator in NHGRI's Medical Genomics and Metabolic Genetics Branch, NIH director and a corresponding author on the paper. "The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.

The toll of this devastating illness on affected children and their families cannot be overstated.The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.

The study follows another recent milestone for progeria research, as the U.S. Food and Drug Administration approved the first treatment for progeria in November 2020, a drug called lonafarnib. The drug therapy provides some life extension, but it is not a cure. The DNA-editing method may provide an additional and even more dramatic treatment option in the future.

David Liu, Ph.D., and his lab at the Broad Institute developed the base-editing method in 2016, funded in part by NHGRI.

"CRISPR editing, while revolutionary, cannot yet make precise DNA changes in many kinds of cells," said Dr. Liu, a senior author on the paper. "The base-editing technique we've developed is like a find-and-replace function in a word processor. It is extremely efficient in converting one base pair to another, which we believed would be powerful in treating a disease like progeria.

To test the effectiveness of their base-editing method, the team initially collaborated with the Progeria Research Foundation to obtain connective tissue cells from progeria patients. The team used the base editor on theLMNAgene within the patients cells in a laboratory setting. The treatment fixed the mutation in 90% of the cells.

The Progeria Research Foundation was thrilled to collaborate on this seminal study with Dr. Collinss group at the NIH and Dr. Lius group at Broad Institute, said Leslie Gordon, M.D., Ph.D., a co-author and medical director of The Progeria Research Foundation, which partially funded the study. These study results present an exciting new pathway for investigation into new treatments and the cure for children with progeria.

Following this success, the researchers tested the gene-editing technique by delivering a single intravenous injection of the DNA-editing mix into nearly a dozen mice with the progeria-causing mutation soon after birth. The gene editor successfully restored the normal DNA sequence of theLMNAgene in a significant percentage of cells in various organs, including the heart and aorta.

Many of the mice cell types still maintained the corrected DNA sequence six months after the treatment. In the aorta, the results were even better than expected, as the edited cells seemed to have replaced those that carried the progeria mutation and dropped out from early deterioration. Most dramatically, the treated mice's lifespan increased from seven months to almost 1.5 years. The average normal lifespan of the mice used in the study is two years.

As a physician-scientist, its incredibly exciting to think that an idea youve been working on in the laboratory might actually have therapeutic benefit, said Jonathan D. Brown, M.D., assistant professor of medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. Ultimately our goal will be to try to develop this for humans, but there are additional key questions that we need to first address in these model systems.

Funding for the study was supported in part by NHGRI, the NIH Common Fund, the National Institute of Allergy and Infectious Diseases, the National Institute of Biomedical Imaging and Engineering, the National Institute of General Medical Sciences, the National Heart, Lung and Blood Institute and the National Center for Advancing Translational Sciences.

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DNA-editing method shows promise to treat mouse model of progeria - National Human Genome Research Institute

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Thomas Leurent on creating an innovation step-change through structural digital twins

For engineers and manufacturers, adapting and improving their product line is an unending task. But eventually, simply tweaking an existing product to tease out another few drops of efficiency isnt enough. Sometimes, because of technological advancements or changes in consumer demand, it is necessary to scrap everything and start from scratch. For instance, most of the basic digital services we take for granted today would not have been possible if we had continued with dial-up modem infrastructure. Switching to broadband was a step-change in our digital capabilities and has unlocked a tidal wave of innovation.For the most part, we havent seen the same level of innovation in mechanical and structural engineering. Part of the problem is, when it comes to large assets such as planes or wind turbines, the health and safety consequences of wiping the slate clean can be enormous. Designing a new aeroplane or wind farm from the ground up is a monumental task. Yet as SpaceX demonstrates, embracing new methods and designs can create huge opportunities. For engineers to manage it effectively, they need accurate data, first class modelling capabilities, and an overview of the full lifecycle of current assets so they see how changes in the design will impact performance and operational life. This is why the future of design will depend on next-generation digital twins with full lifecycle management capabilities.

Tweaking an existing product is often significantly easier and cheaper for companies. However, the problem comes when companies end up tweaking a product line long enough that engineers then have to build around outdated features. When Boeing introduced a low-to-the-ground design for its 737-100 in 1968, it was beneficial but, as technology moved on, it became an increasingly problematic design aspect that engineers had to compensate for.

Continually modernising the 737, rather than starting afresh with a clean design, is part of the reason why the company ended up having to halt delivery of the Boeing 737 Max aircraft last year after the Federal Aviation Administrations decision to ground the aircraft. In contrast, by ditching the single-use model for rocket design and prioritising reusability, SpaceX has realistic ambitions to reduce the cost of reaching Earth orbit by a hundredfold. Currently, no other firm can match SpaceX prices, yet Musk is predicting further cost efficiencies while continuing to improve performance.

Yet starting afresh is also tricky due to the lack of data of how a new design will perform. For example, if an offshore wind farm operator wanted to revamp the type of turbine they use, they are immediately faced with a host of problems, including how the balance of the blades would be affected, or whether joints will be placed under unexpected stress levels and suffer from excessive fatigue.This fear of the unknown is driving many asset manufacturers to continue on an incremental innovation path with enormous over-engineeringespecially because high costs and long duration of physical tests typically allows firms to conduct only a few design iterations. Addressing the problem requires the deployment of next-generation digital twins thatare used throughout the entire lifecycle of assets, from design and fabrication, to operations, to life extension, and finally decommissioning. This enables efficient, lean designs to be implemented, with the knowledge that the digital twin will be used to monitor the asset during operations to pre-emptively identify any issues to avoid failures and downtime. Crucially, the insights gleaned from each digital twin are fed into the next generation of designs, enabling further improvements and optimisations.

Having a full-scale digital twin enables engineers to model potential changes to an assets structure and design, complete with insights into the consequences of those changes. For example, considering the environmental issues that have been caused by wind turbine blades once theyve reached their end-of-life, manufacturers are looking at alternative materials compatible with the circular economy.

However, there is a problem, in that there isnt enough real-world failure data from large turbines for engineers to develop effective, streamlined prototypes. This tends to lead to overly conservative designs, when the exact opposite is required. The solution is the simulation capabilities of next generation digital twins which, because of their full life-cycle management capabilities, can link operations and design in new ways, dramatically speeding up the Return on Experience (REX) for engineers, allowing them to go from a single prototype to the mass deployment of thousands of units within a few short years.

Through the digital twin, engineers can gather data from assets in operation and use it to unlock new possibilities, such as leaner designs with adjusted safety margins based on sensor feedback. Engineers can review how these changes affect performance, efficiency, and lifespan of both the new blades and the asset as a whole, as operations and design become a mutually reinforcing virtuous circle. For example, due to a lack of data around fatigue for turbine shafts, many designs have been overly conservative and can be re-engineered to reduce weight and costs. This in turn will affect the stress and fatigue life of other sections of the turbine and supporting structure all of which will be visible on the digital twin simulation, allowing engineers to reduce cost at the system level.

Crucially, having a physics-based digital twin enables engineers to operate assets, simulate changes, and experiment with breakthrough designs and revolutionary technologies at scale, with the same level of certainty as they have now for incremental improvements and tweaks. By giving engineers the confidence to be bolder and more innovative with the design of their assets is the key to creating large-scale physical assets fit for the digital era, like the new Airbus SE ZEROe hydrogen-powered plane.

Ultimately, every design has physical limits. As the Boeing example illustrates, features which are initially extremely helpful can, over time, become increasingly problematic. Yet we still have engineers spending time on out-of-date designs, trying to squeeze out the last few efficiency gains, when they should be scrapping them and starting afresh.

Having digital twins operating throughout the entire asset life-cycle from design, to operations, life extension, and ultimately decommissioning offers engineers the ability to create leaner, more efficient designs while also increasing confidence in the performance and lifespan of the asset. We have to unlock the same tidal wave of physical engineering innovation that weve seen in the software world over the past few decades, and next-generation digital twins are the secret sauce that can offer reliable, real-time data to underpin this transformation, bringing everything from energy to transport into the 21st Century.

Thomas Leurent isCEO at Akselos

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Digital twins and design innovation - Engineer Live

Recommendation and review posted by Bethany Smith

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY

Preclinical Characterization of HPN536, a Trispecic, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors A C

Mary Ellen Molloy1, Richard J. Austin1, Bryan D. Lemon1, Wade H. Aaron1, Vaishnavi Ganti1, Adrie Jones1,

Susan D. Jones1, Kathryn L. Strobel1, Purbasa Patnaik1, Kenneth Sexton1, Laurie Tatalick1, Timothy Z. Yu1, Patrick A. Baeuerle1,2,3, Che-Leung Law1, and Holger Wesche1

ABSTRACT

Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol- linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast can- cer. Early signs of clinical efcacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic inter- vention, but therapies with improved efcacy are still needed to address the signicant unmet medical need posed by MSLN- expressing cancers.

Experimental Design: We designed HPN536, a 53-kDa, tri- specic, T-cell-activatingprotein-based construct, which binds to MSLN-expressing tumor cells, CD3e on T cells, and to serum albumin. Experiments were conducted to assess the potency, activ-

Introduction

Redirection of cytotoxic T cells with bispecic antibody constructs for cancer therapy has been validated in the clinic (1-6). Blinatumo- mab is the rst and thus far the only bispecic T-cell engager (BiTE) approved by the FDA (7). T-cell-engaging biologics function by forming an immunologic cytolytic synapse between cancer target cells and T cells, which leads to target cell lysis independent of T-cell receptor (TCR) specicity, peptide antigen presentation by HLA, and T-cell costimulation. Despite the clinical success of blinatumomab for treating relapsed and refractory acute lymphoblastic leukemia, other molecules, including BiTE antibodies, showed only limited activity in the treatment of solid tumors (8, 9). Their short plasma half-life required continuous intravenous infusion limiting their utility for most solid tumor indications. Novel designs for T-cell-engaging antibodies aim at overcoming limitations of the rst generation and are already being tested in clinical trials (10).

The Trispecic T-cell-Activating Construct (TriTAC) design has been specically developed to treat solid tumors (11). TriTACs consist of a single polypeptide chain aligning three humanized, antibody- derived binding domains: a single-domain antibody (sdAb) specic for

1Harpoon Therapeutics, South San Francisco, California. 2MPM Capital, Cam- bridge, Massachusetts. 3Institute for Immunology, Ludwig-Maximilians University Munich, Planegg- Martinsried, Munich, Germany.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

Corresponding Author: Mary Ellen Molloy, Harpoon Therapeutics, 131 Oyster

Point Boulevard, 300, South San Francisco, CA 94080. Phone: 773-318-0796;

E-mail: mmolloy@harpoontx.com

Clin Cancer Res 2020;XX:XX-XX

doi: 10.1158/1078-0432.CCR-20-3392

2020 American Association for Cancer Research.

ity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).

Results: HPN536 binds to MSLN-expressing tumor cells and to CD3e on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN- dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.

Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

a tumor antigen, a sdAb specic for serum albumin for half-life extension, and a single-chain fragment variable (scFv) specic for the CD3e subunit of the TCR complex (11). Their molecular size of 53 kDa is about one-third of that of an IgG. Binding of TriTACs to tumor antigen and CD3e is monovalent, which minimizes off-target CD3e clustering that can potentially lead to nonspecic T-cell activation. The absence of an Fc-gamma domain for half-life extension is functionally compensated by an albumin-binding domain. HPN424 (11) and HPN536, the rst two TriTACs are in phase I clinical testing in hormone refractory prostate cancer and mesothelin (MSLN)-over- expressing solid tumors, respectively.

Human MSLN is produced as a 71-kDa precursor of 628 amino acids, which is expressed as a glycophosphatidylinositol-linked cell surface glycoprotein. Its 31-kDaN-terminal domain is released as a soluble protein, termed as the megakaryocyte potentiating factor (MPF), while the 40-kDaC-terminal domain remains attached to the plasma membrane as mature MSLN (12-14). MSLN expression on normal tissue is conned to the single-cell mesothelial layer covering the surface of tissues and organs of the pleural, pericardial, and peritoneal cavities (13, 15). MUC16/CA125 is a binding partner for MSLN, implicating a role for MSLN in cell adhesion (16, 17). However, the precise physiologic functions of MSLN have not been dened, and MSLN-knockout mice exhibit no detectable phenotype or developmental abnormality (18).

MSLN is overexpressed in many malignancies, including ovarian cancer (13, 15, 19), pancreatic cancer (20, 21), non-small cell lung cancer (22-26),triple-negative breast cancer (26, 27), and mesothe- lioma (28, 29). In triple-negative breast cancer (25) and in lung and pancreatic adenocarcinomas (22, 23, 30), overexpression of MSLN correlates with poor prognosis. Differential expression of MSLN in cancer versus normal tissue has made it an attractive target for MSLN- directed imaging agents and therapeutics (10, 31-33). A challenge in developing MSLN-directed therapeutics is the expression of MSLN on normal mesothelial cells, potentially leading to dose-limiting toxicities.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

Molloy et al.

Translational Relevance

Patients with mesothelin (MSLN)-overexpressing tumors, including ovarian, pancreatic, lung, and triple-negative breast cancer, have a high unmet clinical need. A number of MSLN- targeted therapeutics have been developed that show limited efcacy and safety in clinical trials. HPN536 is a novel, MSLN- targeted, trispecic, T-cell-activating protein construct that can potently redirect T cells to lyse tumor cells and was remarkably well tolerated in nonhuman primates at single doses up to 10 mg/kg, which is far above the expected therapeutic dose level. Our ndings suggest that HPN536 has the potential for high clinical activity and a wide therapeutic window. Its long serum half-life supports once-weekly dosing in humans. Currently, HPN536 is the only MSLN-targeting,T-cell-engaging biologic in clinical testing.

HPN536 specically redirects T cells for potent redirected lysis of MSLN-expressing cancer cells with concomitant T-cell activation. In three different mouse xenograft models, HPN536 induced durable antitumor activity at very low doses. In cynomolgus monkeys, HPN536 was well tolerated, showed a long serum half-life, and elicited signs of target engagement on mesothelial structures.

Materials and Methods

Protein production

Sequences of TriTACs, sdAbs, and extracellular domains of target proteins fused to an Fc domain or a hexahistidine tag were cloned into mammalian expression vector, pcDNA 3.4 (Invitrogen), preceded by a leader sequence. Expi293 Cells (Life Technologies) were maintained in suspension in Optimum Growth Flasks (Thomson) between 0.2 and

8 106 cells/mL in Expi293 media. Puried plasmid DNA was transfected into Expi293 cells in accordance with Expi293 Expression System Kit (Life Technologies) protocols and cultured for 4-6 days after transfection. Alternatively, HPN536 was produced in CHO- DG44 DHFR-decient cells (34). The amount of expressed proteins in conditioned media was quantitated using an Octet RED96 instru- ment with Protein A Tips (ForteBio/Pall) using appropriate puried control proteins for a standard curve. Conditioned media from either host cell were ltered and puried by protein A afnity and desalted or subjected to preparative size exclusion chromatography (SEC) using an AKTA Pure Chromatography System (GE Healthcare). Protein A puried TriTAC proteins were further puried by ion exchange and

formulated in a buffered solution containing excipients. Final purity was assessed by SDS-PAGE by resolving 2.5 mg/lane on TRIS-Glycine

gels and visualized with Simply Blue Stain (Life Technologies). Native purity was also assessed by analytic SEC using a Yarra SEC150 3 mm

4.6 150 mm Column (Phenomenex) resolved in an aqueous/organic mobile phase buffered at neutral pH on a 1290 LC system and peaks were integrated with OpenLab ChemStation Software (Agilent Technologies).

In vitro afnity measurements

Afnities of HPN536 analyte for albumin, CD3e, and MSLN ligands were measured by biolayer interferometry using an Octet RED96 instrument with Streptavidin Tips (ForteBio/Pall). Experiments were performed at 27 C in PBS plus casein in the absence or presence of 15 mg/mL has, as described in Results section and gure legends. Binding sensograms generated from empirically determined ligand

loads, appropriate serial dilutions of known analyte concentrations, and association and dissociation times were then t globally to a one- to-one binding model using Octet DataAnalysis 9.0 software.

In vitro T-cell-dependent cell cytotoxicity and T-cell activation assays

T cells from healthy donors were puried from leukopaks (leuka- pheresis samples, StemCell Technologies) using EasySep Human T Cell Isolation Kits (StemCell Technologies, 17951) following the manufacturer's instructions. All cancer cell lines were obtained from the ATCC, with the exception of OVCAR8 cells, which were obtained from the NCI (Bethesda, MD). Cell lines were passaged a maximum of 36 times after being received from the ATCC. Cell line authentication and Mycoplasma testing were not performed. T-cell-dependent cell cytotoxicity (TDCC) assays were performed as described previously (35). Briey, luciferase-expressing target cells and puried human T cells were seeded per well of a 384-well plate at a 10:1 T cell-to-target cell ratio. Target cell killing was assessed following incubation for 48 hours at 37oC and 5% CO2. Target cell viability was assessed by incubation with the SteadyGlo Reagent (Promega). Luminescence was measured using a PerkinElmer EnVision Detection System. Activated T cells were identied by CD69 and CD25 surface expression (BD Biosciences). Samples were analyzed on a FACSCelesta Flow Cyt- ometer (BD Biosciences). Flow cytometry data were processed using FlowJo v10 Software (FlowJo, LLC).

Binding of HPN536 on MSLN-expressing OVCAR and T cells Cultured cells were incubated with 1 mg/mL HPN536 or anti-GFP

TriTAC (control) for 1 hour. Binding was detected using Alexa647- anti-TriTAC antibody using a FACSCelesta Flow Cytometer (BD Biosciences). The QIFIKIT (Dako) was used according to the man- ufacturer's instructions to estimate the number of MSLN molecules expressed per cell.

Cytokines in the presence of T cells

To measure the cytokines, AlphaLISA Kits were used (PerkinElmer) per the manufacturer's instructions, except that the assays were performed in 384-well plates instead 96-well plates. Plates containing conditioned media from TDCC assays were used for analysis. Plates were read on a PerkinElmer EnVision Plate Reader equipped with an AlphaLISA module.

In vivo mouse efcacy studies

All mouse studies were performed in accordance with the policies of the Institutional Animal Care and Use Committee (IACUC) at

Harpoon Therapeutics and Charles River Laboratories. For TOV21G and HPAFII experiments, NCG (NOD-Prkdcem26Cd52Il2rgem26Cd22/

NjuCrl) mice received subcutaneous coimplants of human cancer cells (5 106) and human T cells (5 106) in 50% Matrigel (BD Biosciences) on day 0. Human T cells were expanded before implantation using Human T Cell Activation/Expansion Kit (Miltenyi Biotec) according to the manufacturer's instructions. Mice were dosed on days 1-15 (HPAFII, Fig. 4A and TOV21G, Fig. 4C) or days 7-16 (HPAFII, Fig. 4B) via intraperitoneal injection. For NCI-H292 experi- ments, NCG mice received subcutaneous coimplants of human cancer cells (1 107) and human peripheral blood mononuclear cells (PBMC;

1 107). Mice were administered HPN536 daily for 10 days starting on

day 6 via intravenous injection. Tumor size was measured twice weekly and calculated using the following formula: tumor volume (mm3)

(w2 l)/2. Percent tumor growth inhibition (%TGI) was dened as the difference between the mean tumor volume (MTV) of the control

OF2 Clin Cancer Res; 2021

CLINICAL CANCER RESEARCH

Rela

HPN536

An

group and the MTV of the treated group, expressed as a percentage of the MTV of the control group.

Exploratory cynomolgus monkey dose range-ndingstudy The pharmacology, pharmacokinetics, and toxicity of HPN536

were evaluated after a single intravenous bolus dose of 0.1, 1.0, or 10 mg/kg HPN536 in one male and one female cynomolgus monkey per group followed by either a 1- or 3-weekpostdose recovery period. The study followed the protocol and standard operating procedures of the testing facility (Charles River Labo- ratories) and was approved by their IACUC. Pharmacologic activ- ity was evaluated by clinical observations, cytokine assessments, ow cytometry, and evidence of target engagement by histology. Two research electrochemiluminescence assays, a functional assay and an anti-idiotypeassay, were used for measuring HPN536 levels in serum. For the functional assay, HPN536 was captured with biotinylated CD3e and was detected with a sulfo-taggedMSLN. For the anti-idiotypeassay, HPN536 was captured with an anti- idiotype antibody recognizing the anti-albumindomain and was detected with a sulfo-taggedCD3e. Toxicokinetic parameters were estimated using Phoenix WinNonlin pharmacokinetic software. A noncompartmental approach, consistent with the intravenous bolus route of administration, was used for parameter estimation.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

HPN536 an Anti-MSLN/Anti-CD3T-Cell Engager for Solid Tumors

Toxicity endpoints included daily morbidity and mortality, daily clinical observations, weekly body weights, daily food consump- tion, clinical pathology (hematology, clinical chemistry, and coag- ulation), and anatomic pathology (gross necropsy, organ weights, and histopathology).

Results

Production, structure, and biochemical characteristics of

HPN536

Recombinant HPN536 has a molecular weight of approximately

53 kDa. A humanized llama sdAb specic for human MSLN is placed at its N-terminus (Fig. 1A). A humanized llama sdAb specic for human serum albumin (HSA) is placed in the middle of the molecule. The C-terminal end contains a humanized scFv specic for the human CD3e subunit of the TCR complex. GGGGSGGGS linkers connect the three binding domains.

HPN536 is produced by eukaryotic cell culture and secreted as a single, nonglycosylated polypeptide. Stability studies subjecting HPN536 to various stress conditions, including multiple freeze thaw cycles and storage at 4 C and 40 C for 2 weeks, suggest the protein is stable and stress resistant (Supplementary Fig. S1). The high stability of HPN536 ensures limited aggregation, which would otherwise lead to

huMSLN

huCD3e

huALB

A

B

MSLN

ALB

MSLN

CD3

ALB

CD3

In vitro anity

Human KD (nmol/L)

0.21

6.6

6.3

measurements

CynoK D (nmol/L)

1.1

6.2

5.6

Mouse (nmol/L)

210

NB

170

HPN536 binding to MSLN-

HPN536 binding to

expressing OVCAR8 cells

See the rest here:
Harpoon Therapeutics : Clin Cancer Res 2021; OnlineFirst version Jan 6, 2021 - Marketscreener.com

Recommendation and review posted by Bethany Smith

2020 was transformative in violent and destructive ways - the pandemic has taken a huge social, medical, cultural, and financial toll on us collectively as a species. As of the writing of this note, COVID-19 has caused the deaths of 1.62 million people, including over 300,000 Americans. Our pandemic coverage has attempted to make simple the complexity of this moment, crystalizing expertise from bioethicists, biochemists, immunologists, virologists, bioengineers, epidemiologists, geneticists, healthcare practitioners, and global health specialists.

That said, we did not abandon our bread-and-butter scientific reporting. Ninety percent of our published stories were about research and stories across the sciences and engineering and that paid off in terms of traffic. We had about 2.7M pageviews in 2020, up 65 percent from 1.6M in 2019. COVID-19 coverage overwhelmed many readers in 2020, and we found our non-pandemic articles were welcomed by readers awash in hot-takes by writers without scientific expertise.

Unlike many other science news outlets that saw outsized growth driven entirely by pandemic coverage, our growth has been organic across all of our topics and channels around 11 percent of our pageviews in 2020 came from COVID-19 coverage. This growth bodes well for us in a shifting science news landscape in the coming years, as climate change drives more of the big news cycles.

We've done our best to stay value-aligned, creating equitable structures for our team and our community of scientist writers. We also make our values transparent to our audiences. The values we stated as the national uprising for Black liberation erupted in the summer of 2020 are still values we fight for in our work as a news media organization. The disparate impact of COVID-19 on BIPOC communities is stark and brutal and we will continue to highlight the violence that research can perpetuate when carelessly designed, implemented, and funded.

In addition to leading Massive Science, I started working at the media organization Science Friday in February of 2020, and shortly after my co-founder Allan Lasser began working at the content management system (CMS) company TakeShape. Massive runs on the TakeShape CMS, and Science Friday's audio products and radio program are mission-aligned with the work that Massive does. We've found that working within these organizations has been helpful in pushing Massive to grow in new directions.

We hope in the next two years to find a home for Massive that is more permanent. The options for Massive are infinite, and it will be our goal to find a safe and equitable place for Massive to continue to grow as an editorial science community and platform.

Communicating science during the pandemic has been an interesting challenge for scientists, news media outlets, and journalists. Thankfully, we had spent three years preparing for this moment. One of our first editors, Dr. Ashely Juavinett, summed the challenge up nicely:

Massive broke its previous monthly traffic record in May 2020. We haven't been able to consistently clear 300,000 monthly pageviews yet, but in comparison to 2019, monthly traffic has remained higher and more constant.

2020 easily broke our yearly traffic record set in 2019. The higher traffic also came with a 12 percent increase in the average time readers spend on a page, from 3:03 in 2019 to 3:25 in 2020, with long-form article time-on-page clocking in at 4:11. We're happy with the increase two minutes is considered the start of the "good" time-on-page range, so increasing at a healthy rate here is wonderful.

Massive's bread-and-butter is always basic science, but 2020 was the year we started doing more explainer articles, specifically focused on trending science news. For instance, in July, months ahead of most outlets, we published a piece explaining what exactly an mRNA vaccine is, and what its pros and cons are. In preparation for the winter holidays, we published a series of explainers on evolution and climate change (a two-parter), that we figured would be fodder for family arguments.

In the past, we've experimented with theme weeks, butwe tried a theme month this year and had a lot more success. In the second half of 2020, we started publishing many more interviews than we have in the past. These include one-offs (like this interview with neuroscientist Yewande Pearse about life extension) and series of interviews, like our collaboration with Science Friday on conversations with prominent women scientists. Massive also kept up with the evolving intersection of politics and science. This includes publishing anonymously-written articles from Black scientists as well as immigrant scientists facing deportation.

The most popular articles were, predictably, articles that explained rumors about COVID or put the pandemic in a different light. Five of the 10 most popular articles of the year were about COVID one explained how the virus initially spread, one debunked a conspiracy theory about the virus's origins, and the #1 most popular article put social distancing behavior in a new light.

None of what we do at Massive would have been possible without the support of the community of scientists who work with us and write with us. None of it would have been possible without the support of our partners, supporters and collaborators. And none of it would happen without the dedication of our community, editorial, and infrastructure teams! They are amazing people and I am so proud of what we've done.

I hope this has given you a sense of what Massive is all about, and how we dealt with the ups and downs of 2020. We're really excited about 2021 and hope you'll stick with us. If you ever have questions or feedback about Massive, please email me directly at nadja@massivesci.com.

Onwards to 2021 with the lessons of 2020 close at hand...

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Massive Science Year in Review: 2020 edition - Massive Science

Recommendation and review posted by Bethany Smith

Pantheras clinical trial sites in Preston, North Manchester and North London began dosing volunteers in the Phase III PROVENT trial which will evaluate AstraZenecas long-acting antibody combination, AZD7442, for the potential prevention of COVID-19.

The double-blind, placebo-controlled trial will include adult volunteers who have no history of COVID-19 and have an increased risk of infection, including those over 60, a BMI of over 30, a chronic medical condition, taking immunosuppressive medications or those more likely to be exposed, such as NHS workers, or those living in shared accommodation, such as students or the armed services.

Pantheras dedicated research sites were selected to take part in the trial because of their experience in enrolling and supporting volunteers. The three sites have put in place strict protocols in place to minimise the risk to both volunteers and staff. This enables the company to continue running clinical trials throughout the pandemic.

The trial of AZD7442 single dose inoculation will run for a year and looks to recruit 5000 volunteers globally. The aim of the trial is to evaluate the safety and effectiveness of a combination of two long-acting monoclonal antibodies - man-made versions of naturally occurring human antibodies of the immune system - in preventing COVID-19 infection.

The "antibody combination" differs from a vaccine as it provides antibodies, rather than prompting the body's immune system to make them.

The treatment is aimed at helping those people with a compromised immune system, who cannot be vaccinated, vaccine hesitant and those who are unlikely to respond to a vaccination.

In the event of any volunteers developing COVID -19 symptoms Panthera will be providing support to the patient and ensuring the study can continue with those individuals safely isolated.

Stuart Young CEO of Panthera commented: We are delighted that we have been chosen to enroll volunteers in this critical study. We have taken great care in making sure our sites are as safe as possible for both volunteers and staff so that clinical trials can continue. This is vital in ensuring that there are new medications available to prevent and treat, not only COVID-19, but the many other conditions which afflict so many people.

AstraZeneca's LAAB combination, AZD7442, has been engineered with AstraZeneca's proprietary half-life extension technology to increase the durability of the therapy for six to 12 months following a single administration. The inoculation combines two LAABs which are designed to increase the potency and reduce the risk of resistance being developed by the SARS-CoV-2 virus.

About Panthera Biopartners an Independent Site Management Organisation

Panthera Biopartners was founded by Dr Ian Smith founder of Synexus - and Professor John Lyon previously senior executive in Covance and serial entrepreneur - to provide CROs and pharma clients with services relating to the recruitment and running of clinical trials at customised clinical trial sites by GCP trained healthcare professionals.

Panthera has a growing network of sites across the UK managing studies in a variety of conditions in both primary care settings and hospital sites running trials in key secondary care conditions such as CNS, oncology and NASH with specialist investigators.

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Panthera began dosing volunteers in AstraZeneca's phase III of its long-acting antibody combination AZD7442 for the prevention of COVID-19 at its...

Recommendation and review posted by Bethany Smith

TRUMPS DESPERATE ENDGAME: With the Senate poised to possibly flip to the Democrats and Congress set to certify President-elect Joe Bidens 306-232 Electoral College win later today, President Trump is mounting a final rearguard assault on the constitutional process and will tell thousands of supporters rallying near the White House this morning that he expects Vice President Mike Pence to deliver the victory to him.

In a statement last night, Trump denied reports that Pence had rebuffed his entreaties to intervene to stop Biden from taking office and insisted Pence can act on his behalf. The Vice President and I are in total agreement that the Vice President has the power to act, he said, calling election returns in contested states corrupt and illegal.

Trump said Pence could either send some results back to states for review or simply decertify the results and throw the election to the House of Representatives, where Republicans would have the advantage because each state gets only one vote. Even Trumps own lawyers say that would be unconstitutional.

THE ANGRY CROWD: President Trump has promised to address his supporters personally later this morning at a "March to Save America" rally just south of the White House.

I will be speaking at the SAVE AMERICA RALLY tomorrow on the Ellipse at 11AM Eastern. Arrive early doors open at 7AM Eastern. BIG CROWDS! he tweeted.

Yesterday, hundreds of supporters gathered in Freedom Plaza many without masks and stayed into the night as temperatures dropped to the low 40s and a steady rain fell.

Among the speakers was former national security adviser retired Lt. Gen. Michael Flynn recently pardoned by Trump, who told the crowd, We stand at a crucible moment in United States history.

The rally opened with one speaker shouting F--- ANTIFA for several minutes, long attacks on George Soros, unspecified links to Hugo Chavez and U.S. democracy, and lots of COVID-19 deniers, reported Tom Squitieri of Talk Media News. Who here is up to the task of not wearing a mask? ... Jesus is king and its time to let freedom ring, one speaker goaded, as he gave website directions for anti-COVID wonder drugs and urged the crowd to hug each other, he reported.

UNARMED, CLEARLY MARKED: Meanwhile, the 340 D.C. National Guard troops requested by Washington, D.C., Mayor Muriel Bowser are taking great pains to avoid the confusion of last June, when various law enforcement personnel wore military-style camouflage as they moved against mostly peaceful protesters in Lafayette Square. Many observers thought the Guard had moved against their fellow citizens.

A video released by the Guard shows the troops in support of local police, helping to direct traffic and control crowds, and importantly sporting black identification vests that clearly identify them as National Guard, including their names. The black identification vest is not body armor nor a tactical vest, the Guard said in a statement.

And they are unarmed and not equipped with riot shields or batons. We've explicitly been told there is no weaponry of any kind for this mission, a Guard spokesman told the Washington Examiners Abraham Mahshie. If anything came to that, yes, they would have to facilitate transportation back to the armory.

ANTIFA THE REAL PROBLEM: While half-a-dozen protesters were arrested yesterday on various charges, including possession of guns and ammunition and in one case, assaulting a police officer, the White House issued a statement which made no mention of the armed supporters clashing with local police, instead accusing antifa activists, who werent there, of domestic terrorism.

Despite the lack of any significant counterprotesters, the statement from press secretary Kayleigh McEnany said Trump has signed a memorandum to ensure that Federal officials assess actions of Antifa activists in light of Federal laws that restrict the entry of aliens associated with terrorist organizations and aliens intent on criminal activity.

President Trump will not allow Antifa, or any terrorist organization, to destroy our great country, she said.

Good Wednesday morning and welcome to Jamie McIntyres Daily on Defense, written and compiled by Washington Examiner National Security Senior Writer Jamie McIntyre (@jamiejmcintyre) and edited by Victor I. Nava. Email here with tips, suggestions, calendar items, and anything else. Sign up or read current and back issues at DailyonDefense.com. If signing up doesnt work, shoot us an email and well add you to our list. And be sure to follow us on Twitter: @dailyondefense.

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HAPPENING TODAY: WILL HE OR WONT HE? There will be high drama at this afternoons joint session of Congress to certify Joe Bidens win. The big question: How will Mike Pence, serving in his role as president of the Senate, handle what could be the final loyalty test from Trump.

Pence has a largely ceremonial role, opening the sealed envelopes from the states after they are carried in mahogany boxes used for the occasion, and reading the results aloud, noted the Associated Press. But he is under growing pressure from Trump to tip it to the presidents favor, despite having no power to affect the outcome.

Trump tweeted this morning: If Vice President @Mike_Pence comes through for us, we will win the Presidency.

VETERANS DEADLIEST FOE: We learned this week from the Department of Veterans Affairs (first reported by Military Times) that the number of veterans who have died from COVID-19 has now surpassed total military deaths in the Iraq and Afghanistan wars combined.

The latest figures on the VA website show 6,929 deaths, compared to 6,756 military deaths from Operation Iraqi Freedom (2003 to 2010) and Operation Enduring Freedom (2001 to 2014).

This is obviously a national crisis and one that extends far beyond the veteran community. But the effects on Americas veterans are emblematic of the deteriorating situation and also indicative of where a well-led Department of Veterans Affairs could be contributing to the national recovery, said Jeremy Butler, CEO of Iraq and Afghanistan Veterans of America. Those hardest hit by the pandemic are elderly, those in nursing homes, those with co-morbidities and minorities all demographics that are widely represented by the nations veteran community.

MORE BIDEN PICKS: President-elect Biden plans to nominate Wendy Sherman, the chief U.S. negotiator of the Iran nuclear deal, to be deputy secretary of state, according to published reports.

The No. 3 job at the State Department is expected to go to former department spokesperson Victoria Nuland, who served under Secretary of State Hillary Clinton.

A former Washington Post reporter, Jon Finer is in line to be deputy national security adviser, according to the Washington Post, citing two people familiar with the decision. Finer is a former director of policy planning at State.

Former Brookings Institution fellow Amanda Sloat, who was deputy assistant secretary of state for Southern Europe and Eastern Mediterranean, is reportedly Bidens pick for senior director for Europe on the NSC, says Politico, which was first to report the potential nominations.

CHINA RAIDS: China has conducted a massive round-up of roughly 50 pro-democracy activists in Hong Kong, making the arrests under a new national security law, in what many see as a sign of Beijings willingness to crush opposition forces in the former British colony.

Chairman Xi sees a divided and distracted America, and he isnt wasting the moment, said Republican Sen. Ben Sasse, a self-described China hawk, in a statement. These despicable raids expose the Chinese Communist Party for the cowardly dictators they are.

Those targeted appeared to include all candidates who had run in an unofficial opposition primary last year ahead of an expected election for Hong Kongs legislature, reported the Associated Press.

HOW DO YOU MEASURE SUCCESS? President Trumps top border official says the president fulfilled a promise to install 450 miles of border wall along the U.S.-Mexico boundary by the end of 2020. But upon closer examination, the actual figure for new border barriers is closer to 40 miles.

The construction represents a partial fulfillment of Trump's campaign promises, reports Anna Giaritelli, Washington Examiner Homeland Security Reporter. Trump vowed as a candidate to put up 1,000 miles of wall on the nearly 2,000-mile border, which stretches from the Pacific Coast in California to the Gulf of Mexico in Texas. He also said he would get it done for $4 billion. To date, 738 miles of border wall has been funded for $15 billion. Four hundred and fifty miles of the 738 have been completed.

But Giaritelli notes, More than 340 miles of the 450 total newly installed miles are in the place of older fencing, while 40 miles are brand new in previously unsecured areas. The remaining 50-plus miles are secondary fencing or duplicate barriers put up behind the main fence.

STANDOFF NUKE NEEDED: The Heritage Foundation is out this morning with an analysis of the need for the U.S. to modernize its nuclear air-launched cruise missile to sustain the air leg of the nuclear triad.

Patty-Jane Geller, whose portfolio at Heritage is nuclear deterrence and missile defense, argues that fielding the Long-Range Standoff Weapon, or LRSO, will help deter adversaries and assure allies.

The LRSO will also contribute to both the credibility of U.S. deterrence and the United States extended deterrence commitments to allies and provide a hedge against both technical failure as well as an uncertain geopolitical environment, she writes.

Key points:

Washington Examiner: DC National Guard will be unarmed for Electoral College protests after George Floyd failures

Washington Examiner: Trump hits 450-mile goal for 2020 border wall construction

Washington Examiner: Iran submits second Interpol request to arrest Trump

Washington Examiner: SolarWinds hack likely an active Russian intelligence-gathering effort, US spy agencies say

Washington Examiner: China tightens censorship rules despite pandemic backlash

USNI News: Hospital Ship USNS Mercy Tied Up in Maintenance, Cant Deploy for COVID Relief

AP: Kim opens North Korean congress by admitting policy failures

Reuters: China Says It Will Respond To Planned Taiwan, U.S. Defense Talks

Air Force Magazine: STRATCOM Welcomes Nuke Review, but Says Minuteman III Life Extension Should Not be Considered

USNI News: STRATCOM: U.S. Needs Broader-Based Strategic Review To Assess Threats

Breaking Defense: Navy Secretary: US Weighing Patrols Near Russian Arctic Bases

Wall Street Journal: Russias Neighbors Rebuild Defenses

Reuters: China Urges Calm And Restraint After Iran Enrichment Announcement

Washington Post: Iran: Seizure of S. Korean Tanker Is Not Hostage-Taking

Navy Times: SECNAV Not Sure When Nimitz Strike Group Will Come Home

Bloomberg: Pentagon Gets Diversity Watchdog In Bill Passed Over Trump Veto

Washington Post: Trumps Final Efforts To Overturn Election Create Discomfort For The Military

Newport News Daily Press: Navy SEAL Team 6 Member To Plead Guilty In Death Of Green Beret

Just the News: First female Green Beret charged in Colorado with accidentally shooting into neighbor's apartment

Forbes: Opinion: Why Getting Rid Of U.S. ICBMs Could Make Nuclear War More Likely

Bloomberg: Opinion: James Stavridis: Irans Provocations Are A Warning Shot To Biden

WEDNESDAY | JANUARY 6

11 a.m. Washington Post Live "New Government" webinar on "critical issues facing America, with former Defense Secretary Chuck Hagel; and former Commerce Secretary Penny Pritzker, founder and chairman of PSP Partners. https://www.washingtonpost.com/washington-post-live

12 p.m. Hudson Institute webinar: U.S.-India Defense Ties: Partnership of the 21st Century, with former Indian Integrated Defense Staff Chief Vice Adm. Shekhar Sinha; Abhijnan Rej, security and defense editor at the Diplomat and director of research at Diplomat Risk Intelligence; and Aparna Pande, director of the Hudson Initiative on the Future of India and South Asia. https://www.hudson.org/events

1 p.m. Senate Chamber House and Senate meet in a joint session to count electoral votes of the 2020 presidential election.

4:30 p.m. Intelligence National Security Alliance virtual discussion: The Space Force's intelligence priorities, with Air Force Maj. Gen. Leah Lauderback, Space Force director of intelligence, surveillance and reconnaissance. https://www.insaonline.org/event

THURSDAY | JANUARY 7

1 p.m. Center for the National Interest webinar: Facing the Realities of International Cyber Conflict, with Milt Bearden, distinguished non-resident fellow at the Center for the National Interest; George Beebe vice president and director of studies at the Center for the National Interest; Paul Kolbe, director of the Intelligence Project at Harvard Universitys Belfer Center; and former Undersecretary of Defense Dov Zakheim, vice chairman of the Center for the National Interest. https://us02web.zoom.us/webinar/register

1 p.m. Atlantic Council webinar: Women's Gains in Afghanistan: Supporting Economic Opportunities for Afghan Women as a Driver of Peace and Security, with Ambassador-at-Large for Global Women's Issues Kelley Currie; Brig. Gen. Kimberly Colloton, commander of the Army Corps of Engineers; Connie Duckworth, chairman and CEO of ARZU Inc.; Razia Jan, founder and CEO of Razia's Ray of Hope Foundation; and Sara Greengrass, executive director of the U.S.-Afghan Women's Council. https://www.atlanticcouncil.org/event

5 p.m. George Mason University National Security Institute NatSec Nightcap with Amb. Rosemary Banks, New Zealand Ambassador to the U.S.; and Jamil Jaffer, founder and executive director, National Security Institute. https://nationalsecurity.gmu.edu/natsec-nightcap

FRIDAY | JANUARY 8

9 a.m. Center for Strategic and International Studies virtual discussion: Countering Unmanned Aerial Systems: The Path Forward, with Army Maj. Gen. Sean Gainey, deputy director of Force Protection (J-8) Joint Staff; Nicole Thomas, division chief for strategy and policy at the Joint C-sUAS Office; and Tom Karako, director of the CSIS Missile Defense Project. https://www.csis.org/events

10 a.m. Johns Hopkins University School of Advanced International Studies virtual discussion: Did Russia just attack the U.S.? How should the Biden Administration respond? A conversation about the SolarWinds Hack, with Thomas Rid, professor of strategic studies at Johns Hopkins University and author of "Active Measures: The Secret History of Disinformation and Political Warfare"; and Eliot Cohen, SAIS dean. https://sais.jhu.edu/campus-events

This nation has never before had to face the prospect of two peer, nuclear-capable adversaries who have to be deterred differently, and actions done to deter one have an impact on the other This is way more complicated than it used to be.

U.S. Strategic Commander Adm. Chas Richard, on the nuclear challenges posed by Russia and China.

More here:
National Guard troops to take back seat as Trump addresses supporters rallying to his call to overturn the election - Washington Examiner

Recommendation and review posted by Bethany Smith

By Sunil Jayasiri

The Sri Lanka Air Force is to increase its air capability including combat aircraft within the year and it has already sent a number of aircraft including fighter jets Kfir and MI-17 for overhaul purposes overseas, Air Force Commander Air Marshal Sudarshana Pathirana said yesterday.

We have already initiated discussions with an Israeli Aircraft manufacturer to overhaul five Kfir fighter jets of the Sri Lanka Air Force and within this month all will be finalised on this, the Commander told the Daily Mirror.

He also said that the Cabinet of Ministers had already approved a proposal costing $49 million to overhaul and upgrade five Kfir fighter jets, which were in active service in the SL Air Force.

Air Marshal Pathirana also said that two C-130 aircraft (medium lift transport aircraft) of the SLAF will also be sent for overhaul purposes soon.

Discussions are underway with Pakistan and most probably one C-130 will be sent there for overhauling while bids have already been called for Capital Overhauls and Service Life Extension for the second C-130 aircraft. He also revealed that three Ukraine built Antonov-32 transport aircraft of the SLAF have already been sent to Ukraine for overhaul purposes while another AN-32 will also be sent there soon for the same purpose. Three more MI-17 combat helicopters, that were too on active duty during last two decades had already been sent to Lithuania for overhaul purposes. There were several MI-35 combat helicopters, which are currently grounded and they will also be sent for overhaul and service life extension, the Commander revealed.

Meanwhile, the Air Force Chief said that the SLAF is going to soon purchase two Chinese Y-12 aircraft, which are to be used for several purposes including transport, training, search and rescue missions.

He also said that four more small helicopters that are to be used for training purposes would be purchased and already bids are called for it. For that purpose, we have received the Cabinet approval already, he said.

Visit link:
Several AF fighter jets, combat helicopters to be overhauled to boost air power - Daily Mirror

Recommendation and review posted by Bethany Smith

At the molecular level all cancers are genetic, they start as your normal breast cell or ovaries and overtime pick up small genetic changes. When talking about inherited testing or hereditary testing only a small portion of cancer can be passed down in a family. We roughly quote 5-10% can be due to hereditary reasons or something we might find in an inherited genetic test, explained Dr. Tong at the CURE Educated Patient Womens Cancer Summit.

Genetic testing is a critical part of understanding these cancers, as well as how to treat, and Ill be discussing today about how we think about how genetics fits in cancer development, how genetic testing plays a role and how genetic counseling can help induvial and families come to decisions around genetics, says Dr. Tong.

Some exceptions include, up to 20% of negative breast cancers that can be hereditary and up to 25% of ovarian cancers can be hereditary, which is why genetic testing is recommended for all ovarian cancers.

When talking about hereditary cancer Dr. Tong says clinicians and genetic counselors are thinking about if that person has a higher chance of developing cancer, because nobody is at a 0% of developing cancer. Genetic testing will look at to see if they can identify what is elevating the persons risk of developing cancer, and can you potentially explain why a person developed certain cancer.

Part of what we learn from genetic testing, is not only could it have been due to a hereditary cause, such as a mutation in a gene, but which gene mutation and how can we differentially take care of people depending on which gene mutation did cause that, says Dr. Tong.

Guidelines recommend that all women diagnosed with epithelial ovarian cancer and breast cancer should be offered genetic testing.

Beginning in 2015 technology has brought three different types of gene testing or as they call it, Multi-Gene Panel Testing. Then there is a decision about how much genetic testing to do. For genes that they know are associated with inherited risk, those are high and moderate risk genes, they have actionable guidelines for treatment, risk reduction or prevention.

As technology develops you think about if the low-risk genes should also be looked at, the most likely have no impact on your health, such as a recessively inherited cancer risk, the information from these genes may be relevant to your family members or future generations. Some panel offers looking at newly described genes, they have limited evidence that they may impact inherited cancer risk, and they dont have actionable guidelines yet but could in the future.

We think that pretest counseling with a genetic counselor can help an induvial better understand how genetics impacts or plays a role in their cancer diagnosis or in their family history. Genetic counselors will take a look at family history and go many generations to look at distant relatives to see if there is a pattern to the cancers of that family that can be inherited, or does it look more like sporadic risks, then that counselor can discuss what the testing options are, how much testing to have or if its even right for you or not, says Dr. Tong about genetic testing counseling.

Types of results include a negative, the most important to be working with a genetic counselor, meaning there was no change found in the gene, it is considered a normal result and cancer treatment, screening and prevention decisions can be based on personal and family history of cancer. The next is a variant or uncertain significance, also considered a normal result, a change was found but is most likely due to normal human variation. The last result is positive result, where they find a change or genetic mutation that is associated with cancer, cancer treatment, screening and prevention decisions will be based on the risks specific to the change found.

Some may fear that they may be discriminated against due to their genetic testing results. There are laws in place that will protect you and your family members from employment or health insurance discrimination such as the Genetic Information Non-Discrimination Act of 2008, or GINA. In addition, there is the Americans with Disabilities Act, ADA, and the Health Information Portability and Accountability Act, HIPPA. However, there are limitations, how these laws dont protect against other types of discrimination such as life insurance, disability or long-term care, which would be discussed in your genetic counseling session.

Genetic testing can help thinking about what the path forward is for you and your family when we do learn the results, Dr. Tong concludes. He says going to a genetic counselor can help medically keep you healthy and also emotionally, connecting you with different resources and support organizations.

See more here:
What is Genetic Cancer Testing and How Do Patients Get Tested? - Curetoday.com

Recommendation and review posted by Bethany Smith

DUBLIN--(BUSINESS WIRE)--The "Preimplantation Genetic Testing Market - Growth, Trends, and Forecast (2020 - 2025)" report has been added to ResearchAndMarkets.com's offering.

The preimplantation genetic testing market studied was anticipated to grow with a CAGR of 10.5% during the forecast period.

The major factor attributing to the growth of the market is a rising awareness among parents regarding advancements in diagnostics with a huge volume of neonatal deaths due to complications during childbirth. The growing prevalence of congenital genetic diseases like Edwards syndrome, and common pediatric respiratory disorders such as pneumonia, and asthma are observed in recent years.

Key Market Trends

HLA Typing by Application Segment is Expected to Hold the Major Market Share in the Preimplantation Genetic Testing Market

The HLA typing by application segment is expected to account for the largest held the largest of the pre-implantation genetic testing market. Dominance can be owing to a rising volume of patients with damaged bone marrow or defective immune system. This results in an increased volume of hematopoietic stem cell transplantations (HSCT), necessitating the tests. Also, their increased application in evaluating interconnected matched donors and unrelated donors for safer HSCT is expected to drive the growth of the segment.

On the other hand, inherited genetic disease testing is anticipated to witness the highest CAGR during the forecast period. The lucrative growth can be due to their ability to detect diseases in offspring and increased awareness among the public about the inheritance of these diseases by future generations. Furthermore, steep rising incidences of inherited genetic diseases, such as Marfan syndrome, cystic fibrosis, fragile X syndrome hemoglobin disorders, and others, are driving the growth of the segment.

North America Dominates the Market and it is Expected to do the Same in the Forecast Period

North America is expected to dominate the pre-implantation genetic testing market. The dominance is owing to a growing volume of chromosome abnormality cases leading to various genetic disorders. Aneuploidy is the most common causing Down syndrome among newborn babies in the united states, which holds the major revenue share in the North American market. According to the World Health Organization report published in 2018, down syndrome continues to be the most common chromosomal disorder affecting 6,000 babies born in the United States each year.

This, in turn, resulted in high demand for earlier diagnosis to identify the genetic defects in embryos drive the market in the region. Launch of new products by key players and a rise in improvements in healthcare infrastructure in the United States generates more revenue. Rise in government initiatives to create awareness in public and growing preference among couples for these tests during IVF and other artificial insemination procedures further stimulate the growth of the preimplantation genetic testing market in the region.

Competitive Landscape

The preimplantation genetic testing market is moderately competitive and consists of several major players. Few of the key players dominating the market are following various strategies like an increased focus on R&D and the launch of new products. In October 2019, PerkinElmer launched PG-Seq Rapid Non-Invasive Pre-implantation Genetic Testing Kit for Aneuploidy (PGT-A). It is a non-invasive alternative to conventional IVF embryo biopsies, which is expected to impact the market positively. Some of the major companies currently dominating the market are The Cooper Companies Inc., Illumina Inc., Thermo Fisher Scientific Inc., PerkinElmer Inc., and Bioarray SL.

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS

4.1 Market Overview

4.2 Market Drivers

4.2.1 Increasing Burden of Genetic Diseases Like Patau Syndrome, Edwards Syndrome, and Down Syndrome

4.2.2 Increased Government Initiatives to Create Awareness and R&D Activities to Develop Advanced Diagnostic Devices

4.3 Market Restraints

4.3.1 Small Size of Study Population and Ethical Concerns

4.3.2 Highly Expensive Testing Procedures

4.3.3 Unfavorable Regulatory Framework and Challenges During Development Stage

4.4 Porter's Five Forces Analysis

5 MARKET SEGMENTATION

5.1 Test Type

5.1.1 Preimplantation Genetic Diagnosis (PGD)

5.1.2 Preimplantation Genetic Screening (PGS)

5.2 Product and Service

5.2.1 Instruments

5.2.2 Reagents and Consumables

5.2.3 Software and Services

5.3 Application

5.3.1 HLA Typing

5.3.2 IVF Prognosis

5.3.3 Aneuploidy Screening

5.3.4 Other Applications

5.4 End User

5.4.1 Hospitals and Diagnostic Labs

5.4.2 Maternity Centers and Fertility Clinics

5.4.3 Other End Users

5.5 Geography

6 COMPETITIVE LANDSCAPE

6.1 Company Profiles

6.1.1 The Cooper Companies Inc.

6.1.2 Illumina Inc.

6.1.3 Thermo Fisher Scientific Inc.

6.1.4 Quest Diagnostics Inc.

6.1.5 PerkinElmer Inc.

6.1.6 Invitae Corp.

6.1.7 Natera Inc.

6.1.8 Igenomix Sl

6.1.9 Bioarray SL

6.1.10 Genea Ltd

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/vq1deh

Go here to see the original:
Preimplantation Genetic Testing Market - Global Growth, Trends, and Forecast to 2025: Major Players are The Cooper Companies, Illumina, Thermo Fisher...

Recommendation and review posted by Bethany Smith

Germline testing (GT) is increasingly impacting prostate cancer (PCa) management and screening, with direct effects in urology, medical oncology, and radiation oncology. The majority of testing indications and recommendations center on men with metastatic disease, although guidelines now encompass newly diagnosed, early-stage PCa and entail assessment of personal history, pathologic features, and family history to determine eligibility for testing.

To describe current guidelines on GT for men with PCa and the impact on management. An additional objective was to review the literature on current uptake of GT across practice settings.

A nonsystematic review was performed of current guidelines on GT in PCa from professional societies and consensus conferences, detailing supporting evidence for these recommendations. This was supplemented by a literature review of uptake of GT and precision medicine in practice.

Multiple guidelines and consensus panels recommend GT for men with metastatic PCa. Guidelines endorse BRCA2 testing in metastatic PCa because of strong evidence for PCa risk, aggressiveness, and PARP inhibitor candidacy. Testing of additional DNA repair genes in metastatic disease is also endorsed across guidelines. Immunotherapy with pembrolizumab is an option in some guidelines for men with DNA mismatch repair deficiency. In localized disease, GT is recommended on the basis of histologic features and family history; criteria vary between guidelines. GT for localized disease informs hereditary cancer risk and will probably impact future PCa management. Practice gaps exist regarding utilization of GT.

Germline evaluation is increasingly important in the management of men with metastatic PCa and may also affect the prognosis for men with localized disease. The presence of germline mutations has important hereditary cancer implications for men and their families. Uptake of germline evaluation may be underutilized in some practice settings, so strategies for optimization are required.

Patients with prostate cancer should talk to their doctor about the pros and cons of genetic testing, with attention to family history and cancer features. Genetic testing can have important implications for treatment, cancer screening, and family cancer risk.

European urology oncology. 2020 Dec 31 [Epub ahead of print]

Stacy Loeb, Veda N Giri

Department of Urology and Population Health, New York University and Manhattan Veterans Affairs, New York, NY, USA., Cancer Risk Assessment and Clinical Cancer Genetics, Departments of Medical Oncology, Cancer Biology, and Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: .

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33390340

Original post:
Clinical Implications of Germline Testing in Newly Diagnosed Prostate Cancer. - UroToday

Recommendation and review posted by Bethany Smith

Every drug, from morphine to ibuprofen, has a standard dose -- a sort of one-size-fits all recommendation. But a new study suggests that when it comes to drug doses, "one size fits all" rarely applies.

Stanford Medicine professor Russ Altman, MD, PhD, and a team of scientists found that almost everyone (99.5% of individuals) is likely to have an abnormal or "atypical" response to at least one therapeutic drug. This, at least, is the case for people in the United Kingdom, as the study's data came from the UK Biobank, a project that collects, studies and shares data.

The research found that nearly a quarter of the study's participants had been prescribed a drug for which they were predicted to have an atypical response, based on their genetic makeup. On average, participants were predicted to have an atypical response to 10 drugs.

"Ultimately, the hope is that we can show how pervasive drug response variability is and encourage more doctors to rethink the standard prescription protocols that are largely used today and use genetic testing to predict and adjust forthis variability," said Altman, who is an expert in pharmacogenetics, a field that studies the intersection of drugs and genetics.

An "atypical" drug response encompasses a lot of things; but generally speaking, it means a certain drug might not affect one person the way it does another.

For instance, someone who has an atypical metabolic response might process that drug more efficiently, strengthening its initial effects but decreasing its efficacy over time. On the flip side, it could mean that that person is unable to metabolize the drug at all, leaving them without therapeutic aid, or even with dangerous side effects.

These differences in response to a drug are partially due to our genetics. Specific proteins -- workhorse molecules in the body -- break down drugs in order for the body to benefit from the therapeutic. Those proteins are regulated by a specific group of genes. Natural variation in those genes leads to differences in how an individual's body reacts to a given drug molecule.

Altman and his team, including graduate students and first authors of the study Greg McInnes and Adam Lavertu, analyzed data from nearly 500,000 participants.

For 230,000 participants in the study, the team had primary care data going back about 30 years. That includes which drugs had been prescribed, the dose, and all of the patient's different diagnoses. The researchers also had access to detailed genetic information about each patient. They paid special attention to genetic variations in a group of genes that are known to influence the human drug response.

By comparing an individual's genetics against the variations known to exist in the group of drug-response-associated genes, the researchers could predict how any given patient might respond to a drug.

"Pharmacogenetics as a field has been around for a long time, but it hasn't really been adopted into clinical use," McInnes told me. "It's been growing in the last few years as more people realize the impact that it could have on personalized health. For a long time, it's been this overlooked aspect of genetics that I think is actually one of the most clinically actionable advances that has come out of human genetics."

What's more, he said, the wide variability in the human drug response applies to common therapeutics most everyone has encountered or is familiar with -- ibuprofen, codeine, statins and beta blockers among others.

Moving forward, Lavertu says that the goal is to expand drug-gene variant interaction analyses into more diverse populations. The data from the UK Biobank provided critical insight, but it was largely only representative of a British population, where the majority shares European ancestry. A next step for the researchers is to investigate the same genes in the Million Veteran Program, a government research program with a more diverse study population, that is examining how genes, lifestyle and military exposures affect health and illness.

"Our hope is that doing more of these studies will help us find new relationships between genetic variants and drug response, so that pharmacogenetics can benefit more people," Lavertu said.

Photo byMicha Parzuchowski

Go here to see the original:
Based on genes, nearly everyone is likely to have an atypical response to at least one drug - Scope

Recommendation and review posted by Bethany Smith

Color, which started as a genetic testing service, quickly found a second use for its technology: facilitating Covid-19 testing.

The Burlingame, Calif.-based is working with more than 100 companies and governments to facilitate their testing programs, including Salesforce, United Airlines and the state of California, where it is working with PerkinElmer to process up to 150,000 Covid-19 tests daily.

Now, with $167 million in new funding, the company plans to continue to build out infrastructure for testing and other preventive services.

We realized one of the biggest challenges was how to get healthcare services to people, CEO Othman Laraki said in a phone interview. The Covid-19 crisis brought that focus with a lot of clarity.

Color was founded in 2015, and has since struck several high-profile partnerships. Last year, Alphabets Verily brought in the startup to provide genomic services for participants in its Project Baseline health study. It was also tapped by the NIHs All of Us Research Program to serve as the initiatives nationwide genetic counseling service.

In May, the company received an emergency use authorization to use loop-mediated isothermal amplification (LAMP) technology for Covid-19 testing, which uses a consistent temperature to amplify viral genome segments, instead of the multiple heating and cooling cycles with PCR testing. Two months later, it got the green light to use this technology for unmonitored testing, meaning patients can swab themselves.

Those experiences made Color realize that its biggest value was in this infrastructure that it had created, Laraki said.

People get excited about the science, he said. Really, most of public health is logistics. How do you make basic things available to people where they live and where they work?

With many states still grappling with how they will roll out Covid-19 vaccines to the public, Color also seeks to support that process. So far, the U.S. has grappled with shortages, wasted doses and challenges in determining how to best distribute a vaccine.

Weve had major health needs on the population side for a very long time. Its been death by a thousand cuts. Whats happening here is we are creating an access model for basic services at key social aggregation points: schools, employers, community settings, Laraki said. This is creating a national resource for access and distribution of these services that will outlast the current pandemic.

General Catalyst and T. Rowe Price Associates led the series D funding round, which values Color at $1.5 billion.

The opportunity to design the future of public health through technology cannot be overstated, General Catalyst Managing DirectorHemant Taneja said in a news release. Color understands that often, challenges in healthcare arent scientific or medical in nature, but rather due to access barriers. The hyper-scaling of access is perhaps the most impactful function of digital technology and the fact that Color approaches healthcare from this vantage point makes it among the most important companies in the industry.

Photo credit: aurielaki, Getty Images

See the original post here:
Color hits $1.5B valuation, plans to build on testing infrastructure - MedCity News

Recommendation and review posted by Bethany Smith

Preimplantation Genetic Testing Market Overview: Introduction

Decisive Markets Insights publishes report on Global Market. According to business analysts, the market is anticipated to increase its value and volume over the forecast period 2020 2025 at a compound annual growth rate of x% over the next five years. The industry has witnessed business worth USD xx billion in 2019 and it is set to be at an estimated value of approximately USD xx billion by 2015. The growing trend is due to the market consolidation and widening consumer base and relaxation in the international tariff laws. Dominant players in the market are vying for a bigger share in the pie.

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Brief Summary of the Preimplantation Genetic Testing Market Report

The report covers extensive areas of economic fundamentals to explore the market dynamics. Both macro and micro level aspects have been included to explain the market trends and analyze and forecasts the investment opportunities. All the driving factors have been calculated to deeply delve into the subject of demand and supply chain in the market. To explain the minute structures and complexities of market trends data triangulation research method has been applied through. The challenges and the investment opportunities have also been covered. Other significant factors such as government agencies, socio-political structures, environmental conditions, and cultural norms of the geographies have been enumerated in detail. The report examines market trends on the basis on application areas, product types and key geographies highlighting the market trends.

Preimplantation Genetic Testing Breakdown Data by TypeGenetic Diagnosis/Genetic Screening

Preimplantation Genetic Testing Breakdown Data by ApplicationAneuploidy, Translocations

Preimplantation Genetic Testing Breakdown Data by CompaniesIllumina, Inc. (U.S.), Thermo Fisher Scientific Inc. (U.S.), Agilent Technologies, Inc. (U.S.), PerkinElmer, Inc. (U.S.), CooperSurgical, Inc. (U.S.), and Beijing Genomics Institute (BGI) (China)

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Segmentation and Scope of the MarketMarket segments of the global market have been provided below to understand the bi-furcation of the market. The market segments help the reader to understand the market from all the aspects.

Market Segmentation: Product, Application and Key Geographies

On the basis of product types and application areas, by geographies the market is segmented as North America, Europe, Asia Pacific and the Rest of the World (Row).

These geographical regions are further sub-divided into:

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Preimplantation Genetic Testing Market Segments, Regional and Global Trends, Forecast and Competitive Landscape and Key Players -Inc. (US),...

Recommendation and review posted by Bethany Smith

FLINT, Mich., Jan. 8, 2021 /PRNewswire/ --Forum Health, LLC, a nationwide provider of personalized functional and integrative medicine, has acquired Healing Arts Center, a functional medicine practice based in Valparaiso, Indiana.

This multidisciplinary practice is comprised of an experienced team of providers including a physician, board-certified traditional Naturopath, licensed acupuncturist, nutritionist, chiropractor, and massage therapist. The clinic delivers a broad scope of complementary health services designed to encourage well-being and health in a caring and compassionate environment.

"We are thrilled to welcome the Healing Arts Center team to the Forum Health family. The clinic's patient-focused mission for helping people overcome chronic conditions and lead healthier lives, directly aligns with our philosophy. Healing Arts Center is dedicated to providing the highest level of care possible using Forum Health's holistic and personalized medicine approach," said Forum Health CEO, Phil Hagerman.

With a focus on complementing traditional medicine with alternative health treatments, Healing Arts Center offers a wide variety of services including IV, Chelation and Ozone therapies, acupuncture, reflexology, reiki, craniosacral therapy, massage therapy, hormone testing, allergy elimination, hypnotherapy, and more. They specialize in treating Lyme disease, Parkinson's, dementia, ADD, autism, anxiety, depression, weight loss, allergies, and other specific conditions.

"My team and I are excited to join the growing network of nationwide providers at Forum Health and to offer even more to our existing patients and community," said Dr. Kimberling, founder and lead practitioner of Healing Arts Center.

About Forum Health

Forum Health, LLC is a nationwide provider of personalized healthcare. Steeped in the powerful principles of functional and integrative medicine, Forum Health providers take a root-cause approach to care. They listen and dig deep exploring lifestyle, environment, and genetics to help each patient achieve their ultimate health goals. Members have access to advanced medical treatments and technology, with care plans informed by data analytics and collaborative relationships. To learn more, visitforumhealth.com.

To learn more, visit our practice location page.

SOURCE Forum Health, LLC

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Forum Health, LLC adds Healing Arts Center to its growing community of Integrative and Functional Medicine practitioners - PRNewswire

Recommendation and review posted by Bethany Smith

Big brows are all the rage on runways. But sparse or thinning eyebrows arent uncommon everywhere else. A 2012 research review showed that there are many possible causes of thinning or sparse eyebrows, including:

Lets cover some strategies for filling in and treating eyebrows that have lost some of their fullness.

The easiest way to treat thin eyebrows is to use makeup to make them look thicker and fuller. There are several types of makeup products that you can use to do this, including:

You may want to experiment with a few products, mixing and matching to find the beauty routine that gives you the eyebrow look you want.

To try filling in your eyebrows to make them look fuller, start with these steps:

If you want a remedy thats more permanent than makeup, you can consider these other techniques and treatments for filling in your eyebrows.

You can use semipermanent or permanent hair dye to add a darker pigment to your eyebrows. This can give the illusion of brows that are thicker and fuller.

You can DIY this treatment yourself with drugstore hair dye or go to an esthetician.

A 2017 research review showed that hair loss has been linked to some vitamin deficiencies, including vitamin D and iron deficiencies.

So, it makes sense to think that taking nutritional supplements for vitamin D and iron may help regrow your hair, including at your eyebrows.

Additionally, the same research review above showed that if you dont have a nutritional deficiency, dietary supplements likely wont be effective.

Anecdotally, some essential oils are said to promote hair growth on your head and at your eyebrows.

Be sure to always dilute them with a carrier oil, and do not use oils too close to your eye and on your eyelid. Castor oil and peppermint oil are two anecdotal favorites for hair growth.

Microblading is a cosmetic procedure performed by a licensed provider. The goal of microblading is to make your brows look full and even.

Microblading (and its cousin procedure, nanoblading) does this by making tiny, feather-like strokes that mimic real hair and filling these strokes with a semipermanent pigment.

The results of microblading last 8 to 30 months, after which you will have to get a touch-up if you like the result.

Similar to microblading, microshading is a procedure also performed by a licensed provider.

Unlike microblading, microshading mimics the appearance of a powdered makeup application (in other words, it looks like makeup and not like real eyebrows). Microshading lasts 3 to 6 months.

Semipermanant eyebrow tattoos (such as henna) and regular, permanent tattoos have been around for many years. They often do not look as realistic as microblading.

According to a 2016 study, bimatoprost (Latisse) has not yet been approved by the FDA for the use of eyebrow restoration and would be considered off-label use. The dosage is a topical application to your eyebrows once or twice daily.

This FDA-approved medication for eyelash growth stimulation is by prescription only, and it may take several months to see full results.

Minoxidil (Rogaine) is available as both an over-the-counter and prescription-strength medication. It can be used as a topical foam, a concentrated solution, or be given orally.

In a small 2014 study, 39 participants were asked to use a lotion containing minoxidil on one side of their faces, and a placebo product on the other side in an attempt to treat eyebrow thinning.

The study found that the minoxodil side saw significantly better results than the placebo.

You can talk with a dermatologist or cosmetic surgeon about hair grafts that target your eyebrows. These types of grafts use your existing hair follicles to fill in thin spots and encourage regrowth.

These eyebrow transplant procedures can be quite expensive, require a few weeks of recovery, and there is a risk of serious side effects and infection.

Sparse eyebrows can have several causes.

Overplucking or tweezing your eyebrows can damage your hair follicles and lead to poor hair regrowth. Other causes of sparse eyebrows include:

Hair loss from your eyebrows can be frustrating, but there are lots of available treatments. You can also look into cosmetic procedures and even hair grafts to make your brows look bigger.

If youre concerned about hair loss or cant figure out whats causing it, talk with a doctor.

Continue reading here:
Sparse Eyebrows Treatment, Home Remedies, and Precautions - Healthline

Recommendation and review posted by Bethany Smith

A good nights sleep can do wonders for anyone.

However, this is especially true for aging adults, according to Brandy Delp, executive director of Windsor Heights Assisted Living and Memory Care in Beachwood, and Dr. Mark Levy, owner and founder of Sleep Better Columbus in Columbus.

Hormones tend to change as we get older, which affects all kinds of things like sleep cycles and bathroom needs, Levy said. The hormone changes make you have to use the bathroom more and those needs cause you to have to get up, which disturbs sleep and ultimately wakes you up.

Delp said, As we age, changes in our hormone production occurs such as a decrease in melatonin, which helps promote sleep. Older adults have a harder time falling asleep, have frequent nighttime awakenings and increased difficulty returning to sleep once awakened.

Delp added that age-related sleep patterns also involve earlier bedtimes and early morning rising times, and frequent naps during the daytime hours.

Another change seniors may observe in their sleep patterns stems from breathing issues and changes, Levy said.

As you get older, the tissues in the back of your throat get a little slack and not as firm, he explained. That leads to snoring and sleep apnea. All of that snoring and related events can cause you to stop breathing, which are micro-arousals, and bring you up out of deep sleep.

Sleeping well allows one to start the day refreshed and rested. But why does having enough sleep make people feel so good?

Delp said it is closely related to the processes bodies go through while were at rest, which can be especially important as we age.

Several processes occur during sleeping, such as acceleration of protein synthesis and tissue repair, increased production of growth hormone, as well as cognitive function and memory formation, she said. Sleep plays a vital role in brain function and the immune system along with several other bodily processes.

Levy said, Physically, you need to heal. But mentally, sleep allows you to regroup and process the days events. Your brain needs that time.

For aging adults, lack of sleep can lead to serious health conditions like cognitive issues, Delp noted. Fatigued people also put themselves at risk for falls, as well as mood issues like anxiety, depression and irritability. Levy said lack of sleep can lead to brain fog, which can cause confusion in daily tasks for seniors.

At Sleep Columbus, Levy said patients seek oral appliance solutions for sleep apnea and snoring. Though they cant dispense CPAP machines, they also offer sleep testing out of the office to determine if a patient has sleep apnea.

We do a lot of hand holding and guiding, and were the connector between the things they do to make it better, he said. Were a lot more accessible and basically are the sleep tour guide.

As for Windsor Heights, staff works daily to ensure an optimal nights sleep for residents, according to Delp.

We keep routines for our residents, offer bedtime snacks, close the curtains in the evening, increase physical activity during the daytime and plan quiet activities in the evening, Delp said.

She had other suggestions for seniors struggling with sleep issues.

Exercise regularly, avoid stimulants three to four hours before bedtime such as coffee, chocolate, cigarettes and soda, and dont use electronic devices at least an hour before bed, Delp said.

Those experiencing sleep issues should also consult a physician.

First thing to do is have a conversation with their primary care doctor, and if they suspect sleep apnea, they can call someone like us, Levy said. Recommendation is always the best place to start the process of getting help for any health issue.

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Heres an idea for experiencing restful days sleep on it - Cleveland Jewish News

Recommendation and review posted by Bethany Smith

There's a lot to love about caffeine. First, because it's found in plants, it can actually be said to be all-natural, and those plants, including the ones used to make coffee, tea, and cocoa, are rich in sources of antioxidants and phytonutrients. Caffeine, itself, is a phytonutrient that can help reduce your risk of Parkinson's, dementia, and certain oral cancers, according to the University of Michigan Health Service.

One of caffeine's immediate physiological effects is to speed up your central nervous system, which can help you feel alert and focused. Another is that it increases levels of dopaminewhich is one of those "feel-good" chemicals your body produces that improves your mood.

Consuming moderate amounts of caffeine (up to 400 milligrams per day, or the equivalent of four cups of coffee) has never been scientifically linked to long-term harm in healthy adults. However, that's not to say it doesn't have side effects.

For example, to the extent it can improve your mood, it can also be addictive. And while it can keep you focused, it can also leave you feeling overstimulated, according to registered dietitian Amy Goodson. Read on to learn more about the side effects of drinking caffeine, according to science. And don't forget to check out the 7 Healthiest Foods to Eat Right Now.

"Because caffeine is a stimulant, it increases your heart rate while it's in your system," says general practice physician, Leann Poston, MD. "At the same time, it causes the blood vessels to narrow, which increases the pressure the heart must exert to circulate blood." This sets you up for a temporary spike in blood pressure.

That said, high blood pressure is a serious condition that, over time, can put you at increased risk for heart disease, stroke, and kidney failure, among others. It's also associated with the most serious and even life-threatening presentation of the COVID-19 infection.

The good news is that the rise in blood pressure attributable to consuming caffeine is temporary, according to Sheldon G. Sheps, M.D., via Mayo Clinic. However, if you've been diagnosed with high blood pressure, it's not a bad idea to ask your doctor if you need to limit your intake of caffeinated beverages.

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Most people associate headaches with caffeine-withdrawal. However, a 2004 study published in the scientific journal Neurology found that among people who suffer from chronic daily headaches, a condition in which headaches are suffered at least 15 times per month, a significant percentage had been heavy caffeine drinkers prior to the onset of their chronic daily headaches.

Similarly, among migraine sufferers, caffeine overuse has been associated with an increase in migraine frequency. If you get frequent headaches, you might want to consider cutting some of these headache-triggering foods out of your diet.

"If you are already stressed or anxious, caffeine can make it worse," according to registered dietitian Elisa Bremner. In fact, as little as 100 milligrams of caffeinethe equivalent of one cup of coffeemay exacerbate pre-existing feelings of stress and anxiety. The scientific community offers several reasons for this. One is that the natural effects of caffeine as a stimulant cause a number of physical symptoms that we tend to associate with anxiety, including increased heart and breathing rates. Our bodies may experience those symptoms as anxiety.

In addition, caffeine stimulates the release of adrenaline, Dr. Poston tells Eat This, Not That! Adrenaline is a hormone that prepares us for "fight or flight" when we're faced with stressors. It does so by increasing alertness and raising heart rate, respiration, and blood flow. And because caffeine competes with a chemical called adenosine, which leads to feelings of fatigue and relaxation, the whole combination of all of these effects can lead to distinct feelings of nervousness, jitteriness, and anxiety.

Nevertheless, here is why you might want to consider drinking coffee before taking a nap.

Caffeine consumption has been linked to an increased risk of miscarriage, according to this paper published in 2020 in the scientific journal BMJ. The paper, which consisted of a meta-analysis of 48 existing studies addressing the link between caffeine consumption and negative pregnancy outcomes such as miscarriage, found that drinking coffee while pregnant is, in fact, associated with pregnancy loss.

The reason, according to OB/GYN, Jodie Horton, MD, may be linked to the fact that caffeine narrows blood vessels, which can diminish the transfer of nutrients to the fetus. It's worth pointing out, however, that these findings are at odds with the current recommendations from the American College of Obstetrics and Gynecology, which state that "moderate consumption" of caffeine does not present a miscarriage risk, according to OB/GYN Brittany Noel Robles, MD. Nevertheless, Dr. Robles recommends keeping caffeine to a minimum during pregnancy. (Related: Don't miss these 8 pregnancy myths, busted.)

Caffeine's stimulant effect can help ensure that you'll keep your digestive system "moving."However, for some people, caffeine is too stimulating, which is to say, it can have a laxative effect. In other words, caffeine can cause loose bowels and evendiarrhea. Diarrhea is a major symptom of irritable bowel syndrome, according to Johns Hopkins Medicine's Health Blog.

If you're running to the bathroom every time you have caffeine, it may be worth talking to your doctor about whether you might be suffering from irritable bowel syndrome. Whether or not you are diagnosed, the discussion could lead to you deciding to limit your caffeine intake until you find a level at which consumption does not equal digestive distress.

For more on caffeine, here are 11 surprising ways that drinking tea can heal you.

Read more:
Side Effects of Drinking Caffeine, According to Science | Eat This Not That - Eat This, Not That

Recommendation and review posted by Bethany Smith

publication date: Jan. 8, 2021

FDA has approved Tagrisso (osimertinib) for adjuvant therapy after tumor resection in patients with non-small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Tagrisso is sponsored by AstraZeneca Pharmaceuticals LP.

Efficacy was demonstrated in a randomized, double-blind, placebo-controlled trial (ADAURA, NCT02511106) in patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy.

Eligible patients with resectable tumors (stage IB IIIA) were required to have predominantly non-squamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas EGFR Mutation Test. A total of 682 patients were randomized (1:1) to receive osimertinib 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy, if given.

The major efficacy outcome measure was disease-free survival in patients with stage II IIIA NSCLC determined by investigator assessment. Median DFS was not reached (38.8, NE) in patients on the osimertinib arm compared with 19.6 months (16.6, 24.5) on the placebo arm (HR 0.17 95% CI: 0.12, 0.23; <0.0001). DFS in the overall study population was a secondary efficacy outcome measure; the median was not reached (NE, NE) in patients on the osimertinib arm compared with 27.5 months (22, 36) on the placebo arm (HR 0.20 95% CI: 0.15, 0.27; <0.0001).

Iclusig receives FDA sNDA approval for adult patients with resistant or intolerant chronic-phase CML

FDA has approved the supplemental New Drug Application for Iclusig (ponatinib) for adult patients with chronic-phase chronic myeloid leukemia with resistance or intolerance to at least two prior kinase inhibitors.

Iclusig is sponsored by Takeda Pharmaceutical Company Ltd.

The updated label includes an optimized, response-based ICLUSIG dosing regimen in CP-CML with a daily starting dose of 45 mg and, upon achieving 1% BCR-ABL1IS, dose reduction to 15 mg. This dosing regimen aims to maximize benefit-risk by providing efficacy and decreasing the risk of adverse events, including arterial occlusive events.

The sNDA approval is based on data from the phase II OPTIC (Optimizing Ponatinib Treatment In CML) trial, as well as five-year data from the phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) trial.

The OPTIC trial included patients with CP-CML whose disease was highly-resistant to their immediate prior TKI, the majority of whom (65%) did not achieve a response greater than complete hematological response on immediate prior therapy.

At 12 months, 42% of 88 patients utilizing the newly approved response-based dosing regimen (45 mg to 15 mg) achieved 1% BCR-ABL1IS, the primary endpoint of OPTIC, and at a median follow up time of 28.5 months, 73% of these patients maintained their response. In these patients, 13% experienced an AOE of any Grade, 7% experienced Grade 3 or higher. Risk factors such as uncontrolled hypertension or diabetes should be managed, and caution should be exercised when treating patients with active or substantial history of clinically significant, uncontrolled cardiovascular disease.

Xpovio receives FDA approval for refractory or relapsed multiple myeloma

FDA has approved Xpovio (selinexor) in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

Xpovio is sponsored by Karyopharm Therapeutics Inc.

FDA granted Xpovio accelerated approval in 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Efficacy of Xpovio in combination with bortezomib and dexamethasone was evaluated in the BOSTON Trial (KCP-330-023, NCT03110562), a randomized (1:1) open-label, multicenter, active comparator-controlled trial in patients with RRMM who had previously received at least one and at most three prior therapies.

Patients received once-weekly selinexor orally in combination with once-weekly bortezomib subcutaneous and low-dose dexamethasone twice-weekly orally compared to the standard twice-weekly bortezomib plus low-dose dexamethasone.

The main efficacy outcome measure was progression free survival assessed by an independent review committee using International Myeloma Working Group response criteria. The estimated median PFS was 13.9 months (95% CI: 11.7, Not Estimable) for the SVd arm and 9.5 months (95% CI: 7.6, 10.8) for the Vd arm (estimated hazard ratio 0.70; 95% CI: 0.53, 0.93).

Orgovyx receives FDA approval for advanced prostate cancer

FDA has approved the first oral gonadotropin-releasing hormone receptor antagonist, Orgovyx (relugolix) for adult patients with advanced prostate cancer.

Orgovyx is sponsored by Myovant Sciences inc.

Efficacy was evaluated in HERO (NCT03085095), a randomized, open label trial in men requiring at least one year of androgen deprivation therapy with either prostate cancer recurrence following radiation or surgery or newly diagnosed castration-sensitive advanced prostate cancer. Patients (N=934) were randomized (2:1) to receive relugolix 360 mg oral loading dose on the first day, followed by daily oral doses of 120 mg, or leuprolide acetate 22.5 mg injection subcutaneously every 3 months for 48 weeks.

The main efficacy outcome measure was medical castration rate defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by day 29 through 48 weeks of treatment. The medical castration rate was 96.7% (95% CI: 94.9%, 97.9%) in the relugolix arm.

Margenza receives FDA approval for metastatic HER2-positive breast cancer

FDA has approved Margenza (margetuximab-cmkb) in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Margenza is sponsored by MacroGenics.

Efficacy was evaluated in SOPHIA (NCT02492711), a randomized, multicenter, open-label trial of 536 patients with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Patients were randomized (1:1) to margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting ( 2, > 2), and number of metastatic sites ( 2, > 2).

The main efficacy outcome measures were progression-free survival by blinded independent central review and overall survival. Additional efficacy outcome measures were objective response rate and duration of response assessed by BICR.

Median PFS in the margetuximab arm was 5.8 months (95% CI: 5.5, 7.0) compared with 4.9 months (95% CI: 4.2, 5.6) in the control arm (HR 0.76; 95% CI: 0.59, 0.98; p=0.033). Confirmed ORR was 22% (95% CI: 17, 27) with a median DOR of 6.1 months (95% CI: 4.1, 9.1) in the margetuximab arm compared to an ORR of 16% (95% CI: 12, 20) and median DOR of 6.0 months (95%CI: 4.0, 6.9) in the control arm.

CPI-613 receives FDA Fast Track Designation for treatment of AML

FDA has granted Fast Track designation to CPI-613 (devimistat) for the treatment of acute myeloid leukemia.

CPI-613 is sponsored by Rafael Pharmaceuticals Inc.

Rafael Pharmaceuticals received Fast Track designation for devimistat for the treatment of metastatic pancreatic cancer in November 2020. The company also received Orphan Drug Designation for the treatment of soft tissue sarcoma for devimistat, and the initiation of a phase II clinical trial of devimistat in combination with hydroxychloroquine in patients with clear cell sarcoma of soft tissue.

EU CHMP issues positive opinion for Keytruda as first-line treatment in adult patients in colorectal cancer indication

The Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion recommending approval of Keytruda, Mercks anti-PD-1 therapy, as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.

Keytruda is sponsored by Merck.

This recommendation is based on results from the pivotal phase III KEYNOTE-177 trial, in which Keytruda, as a monotherapy, demonstrated a significant improvement in progression-free survival compared to chemotherapy (investigators choice: mFOLFOX6 with or without bevacizumab or cetuximab; or FOLFIRI with or without bevacizumab or cetuximab), a current standard of care.

Data from KEYNOTE-177 were presented at the virtual scientific program of the 2020 American Society of Clinical Oncology Annual Meeting and were published in The New England Journal of Medicine. The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the first quarter of 2021.Servier and Celsius Therapeutics collaborate on colorectal cancer research

Servier and Celsius Therapeutics have formed a strategic collaboration focused on the identification and validation of novel colorectal cancer drug targets.

Through this collaboration, we will leverage Celsius single-cell genomics platform, machine learning capabilities, and target validation expertise to refine our understanding of the different subtypes of CRC and discover new drug targets with the goal of developing novel precision therapies for specific patient subsets, Hugues Dolgos, global head of oncology research and development at Servier, said in a statement. Servier will discover and develop candidate drugs leveraging our end-to-end small molecule and large molecule capabilities.

Under the terms of collaboration, Celsius will analyze hundreds of samples from defined CRC patient populations using its proprietary single-cell genomics platform and will work to identify and validate new drug targets during the three-year research period. Servier will receive an exclusive option to research, develop, and commercialize products directed to up to three of the targets.

Celsius would receive an upfront payment and research funding, and would be eligible to receive over $700 million in potential discovery, development, and commercialization milestone payments, along with tiered royalties.

Bayer and Veracyte collaborate on precision oncology in thyroid cancer

Bayer and Veracyte have entered a collaboration to advance the Precision Oncology Patient Identification Program in thyroid cancer.

Through the program, Bayer will offer testing with Veracytes Afirma Xpression Atlas to identify underlying genomic drivers, including NTRK gene fusions, within patients tumors. The program will focus on patients with advanced or metastatic thyroid cancer that is radioactive iodine refractory who may potentially benefit from biomarker-driven therapies.

Patients whose thyroid cancer contains actionable alterations and no longer responds to traditional radioactive iodine therapy now have targeted treatment options available to them. Our goal is to identify such patients so physicians can make more informed treatment decisions for their patients, Bhavesh Ashar, senior vice president and head of U.S. Oncology at Bayer, said in a statement. With its comprehensive ability to identify broad genomic alterations through its Afirma XA test and its widespread reach among physicians who diagnose thyroid cancer, Veracyte is an ideal collaborator for this program.

The Afirma XA uses RNA whole-transcriptome sequencing to identify 905 DNA variants and 235 RNA fusions in 593 genes, including novel NTRK fusions, on fine needle aspirates taken from thyroid nodules or lymph nodes.

Through this collaboration, Bayer will provide Afirma XA testing at no cost to all eligible patients when ordered by the physician, regardless of the final results and treatment decision. Additionally, physicians of patients found to harbor NTRK gene fusions as an underlying driver in their thyroid cancer will be alerted of the results. The companies anticipate the program to launch in the first quarter of next year.

Servier to acquire Agios Pharmaceuticals oncology business

Servier has entered into an agreement for the acquisition of Agios Pharmaceuticals oncology business including its commercial, clinical and research-stage oncology portfolio for up to $2 billion, including an upfront payment of $1.8 Billion and a potential $200 million in regulatory milestone, plus royalties.

The transaction has been approved by both companies respective boards of directors. Subject to receipt of regulatory clearances and approval by Agios shareholders, the acquisition is expected to close in Q2 2021.

Servier has made oncology one of its strategic priorities, allocating 50% of its overall research and development budget to this therapeutic area. The acquisition will reinforce Serviers presence in the U.S., where the group has been operating since 2018.

The transaction includes the transfer of Agios oncology portfolio and associated employees, including its marketed medicine Tibsovo, which is approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia and for adults with newly diagnosed IDH1-mutant AML who are 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

Tibsovo is also under investigation in two phase III combination trials in newly diagnosed AML, and as a potential treatment for previously treated IDH1-mutant cholangiocarcinoma and IDH1-mutant myelodysplastic syndrome. Servier will also acquire Agios co-commercialization responsibilities for Bristol Myers Squibbs Idhifa (enasidenib) and conduct certain clinical development activities within the Idhifa development program.

In addition, the transaction includes Agios oncology pipeline and clinical programs, including vorasidenib, an investigational, brain-penetrant, dual inhibitor of mutant IDH1 and IDH2 which is currently being studied in the registration-enabling phase III INDIGO study in patients with IDH-mutant low-grade glioma; AG-270, an investigational first-in-class methionine adenosyltransferase 2a inhibitor being evaluated in combination with taxanes in patients with methylthioadenosine phosphorylase-deleted non-small cell lung cancer and pancreatic cancer; AG-636, a novel inhibitor of dihydroorotate dehydrogenase; and Agios oncology research programs.

All of Agios U.S.-based employees who primarily support the oncology business will receive a comparable offer at Servier.

Kite and Oxford BioTherapeutics establish cell therapy research collaboration in blood cancers and solid tumors

Kite, a Gilead Company, and Oxford BioTherapeutics Ltd. have entered into a research collaboration to evaluate five novel targets for a number of hematologic and solid tumor indications.

Through this collaboration, OBT will validate five novel oncology drug targets, previously identified using OBTs OGAP discovery platform, and generate antibodies against these targets. Kite and Gilead will have the exclusive right to develop and commercialize therapies based on these targets or antibodies.

Under the terms of the agreement, OBT will receive an upfront payment and will be eligible to receive additional payments based on achievement of certain discovery, clinical and regulatory milestones, as well as royalties on future potential sales.

Original post:
Tagrisso receives FDA approval as adjuvant therapy for NSCLC with EGFR mutations - The Cancer Letter

Recommendation and review posted by Bethany Smith

It has not been a good year for sleep. Between a pandemic, social unrest, an election, and the stresses of working (or learning, or teaching) from home, millions of us are experiencing coronasomnia. Thats why two months ago, I started to take a CBN tincture, in hopes that it would combat the hours of blue light exposure and heightened holiday-related anxiety that were plaguing my sleep habits.

With one 50-milliliter drop of Ned Sleep Blendhalf the recommended doseI drifted into a peaceful, uninterrupted sleep for eight full hours (two more hours than usual, for me). Ive since incorporated a half-dropper of Ned into my bedtime routineand while it lacks the instant catalyst that melatonin or over-the-counter medications provide, it settles my mind into a restful, deep sleep as soon as I shut my eyes.

[Photo: courtesy Ned]

We all have hectic days and tend to stay up really late, and our brains get confused about when to be alert, when to be sleepy, and when to be sleeping deeply, explains Dr. Nitun Verma, a San Francisco sleep physician and spokesperson for the American Academy of Sleep Medicine. Once upon a time when we all used to work outdoors, the sun would go down over a period of hours. It would get cooler, darker, quieter, and your brain would get the sense that it was time to go to sleep.

If youre in search of a good nights sleep, dont worryyou can still help your brain recognize its time to wind down just by building out a routine, Verma says. For example, he recommends cleaning up your workstation when youre done with work for the day. That concept helps your brain understand, Hey this activity is over. And now I get to have personal time and to relax. It shows your brain that youre getting ready to sleep.

For the rest of your evening, here are some of our best suggestions for calming down, cozying up, and getting some shut-eye.

[Photo: courtesy Prismatic Plants]Prismatic Plants Goodnight TincturePrismatic Plants Goodnight Tincture combines all the relaxing elements of cannabis without the unwanted side effects: CBD by itself is not sedativewhat it does do is help calm a busy, racing mind, says founder Sarah Polansky. If you need assistance in making your mind and body tired, then CBN is what you will want to take. Good Night features a blend of adaptogens, MCT oil, and terpenes with 300 milligrams of full-spectrum CBD and 10 milligrams of CBNenough to help you doze off, but not so much that you get a cannabis hangover the next morning, Polansky says.

[Photo: courtesy THE WELL]The Well Relax BundleWhether you believe in the power of aromatherapy or just like the scent of lavender, the Wells Relax self-care bundle is an excellent way to wind down at the end of a long day. Staff editor Lara Sorokanich says: Before I get into bed, I spray this all over my pillows and sheets. It feels so luxurious and relaxing to get into a lavender-scented bed. Clinically backed or not, the smell definitely makes me feel happy as Im dozing off.

[Photo: courtesy Oura]Oura RingWhile the Oura Ring might not put you into a deep sleep, it can certainly tell you what happens once you get there. Slip this unintrusive smart band onto your finger to track health progress throughout the day and night; it monitors everything from step count to sleep quality. By automatically measuring your sleep balance against your daily activities via the accompanying Oura app, you can be one step closer to determining daytime habits (looking at you, afternoon coffee) that keep you up at night.

[Photo: courtesy Dohm]Dohm Natural Sound MachinesWhite noise is a city dwellers best friend. The dull hum of a sound machine can help drown out disruptions like construction during the day or noisy neighbors at night without adding to the chaos. The mechanical whirling of white noise works by creating a higher-volume baseline, meaning loud, jarring noises dont make you jump. We like these simple, space-conscious Dohm sound machines that enhance an atmosphere with gentle sleep-inducing noise and sleek, inoffensive design.

[Photo: courtesy The Nue Co.]The Nue Co. Sleep DropsPlant-driven supplement brand the Nue Co.s Sleep Suite includes a tincture, capsules, and a magnesium spray thats absorbed through the skin and can be taken individually or in tandem to best tackle your level of restlessness. My approach to a good nights sleep is to relax and unwind, limiting any screen usage an hour before bed and following the same nightly routine, says Jules Miller, founder and CEO of the Nue Co. I use our Magnesium Ease spray on my joints and stomach. Half an hour before bed, I place 12 Sleep Drops under my tongue to help me to fall asleep. I also like to ensure that the room is in complete darkness to minimize any disruption caused by light.

[Photo: courtesy Uncommon Goods]Moon Beam Sleep AidThis clever, flat disc acts as a sleep-inducing metronome, projecting gentle pulses of blue light onto your ceiling for 8 or 20 minutes. Moon Beams process has a dual purpose: calming your busy mind through distraction and slowing down your breathing and metabolism, readying your body for sleep. Users inhale and exhale in time with the dimming and brightening of the blue glow, eventually drifting from 11 breaths per minute to 6.

[Photo: courtesy Bearaby]Bearaby Cotton NapperWe love the deliciously heavy comfort of the chunky knit Bearaby Cotton Napper. The hype of weighted blankets comes from studies that found the all-encompassing pressure can help release serotonin in the body while reducing the stress hormone cortisol. But unlike fellow weighted blankets on the market, Bearabys beautiful, sustainable throws get their heft from thick woven cord that also serves as a mechanism to keep sleepers from getting sweaty.

[Photo: courtesy Riley Home]RileyReversible Flannel Sheet SetThese cotton flannel sheets from Riley are thick and plush, but breathable enough for those who sleep hot. While perfect sleep temperature is subjective, a layer of lightweight warmth can keep you comfortable all night long in chillier months.

[Photo: courtesy Brooklinen]Brooklinen Mulberry Silk Eye MaskDont underestimate the power of a pitch-black room. While blackout curtains certainly help, the glow of charging electronics and late-night rumblings of my partner and cat can shake me out of a deep sleep in an instant. As far as simple solutions go, a sleep mask makes a huge difference by minimizing disruptions. Even better if its made of luxurious silk, like this one from Brooklinen, that doesnt tug my skin and lashes through a night of tossing and turning.

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"For if one drinks much from a bottle marked 'poison,'it's almost certain to disagree with one sooner or later."Lewis Carroll, "Alice's Adventures in Wonderland"

In the early 16th century, a Swiss physician named Paracelsus changed the course of the healing arts with his theories on chemical treatments for disease. A literal renaissance man given the era, he was part scientist, part alchemist, and part philosopher. Three hundred years before the advent of Pasteur's germ theory, Paracelsus advised patients to keep their wounds clean to avoid infection. His study of chemicals revealed both their curative and harmful properties, and he noted that any treatment turns toxic once the dose is high enough. Paracelsus' simple yet profound insight that "the dose makes the poison" challenged the prevailing wisdom that poisons were inherently toxic. He noted that the known poisons of the day were substances that were toxic at low-doses. Yet, dilute these substances enough and they could be rendered harmless or, in some cases, even beneficial.

This theory is now known as dose response. It has become one of the key frameworks of environmental science, modern medicine, and public health. Put simply, it states that the larger the dose of a chemical or exposure, the greater the magnitude of its effect. Thus, low doses of a toxin can have zero to minimal effect, while large doses become deadly. For therapeutic chemicals, or "drugs," benefits initially rise with increasing doses before crossing a threshold toward toxicity, or overdose.

In modern medicine, dose response theory is foundational for both toxicology and pharmacology, and also carries over to the worlds of microbiology, virology, and oncology. Although in each scenario, the theory is labelled "dose response," its application differs according to the properties of the substance. In recent months, for example, dose response has been hotly debated alongside speculation on the exposure risk of COVID-19. What is the potential for virus exposure via the groceries you buy? What about the mail delivered to your home? Could you get sick from takeout food? The answer lies in the question: how much 'dose' is required to get ill?

A brief history ofdose response theory

For many chemical substances, the dose response theory of toxicity depends on five important variables that predict a subject's response to an exposure:

If you plot the administered dose of a substance versus its effect on a living organism, you often get a "dose response" curve that typically resembles the letter 'S'.

As you can see in the curve, low level exposures may have no effect on an organism up to a certain threshold. For example, many adults are familiar with the toxic effects of drinking alcohol just ask any college student how they feel on Sunday morning. Ripe bananas also contain trace amounts of alcohol, but few individuals eat a banana and worry about their ability to drive home. While a certain dose of alcohol causes intoxication, it has no harmful effect beneath its toxic threshold. As intoxication rises past a second threshold, its effect turns deadly.

Poisons and the canary in the coal mine

The "canary in a coal mine"is a well-known idiom that has a historical antecedent. In the early 20th century, miners brought captive birds with them into the mine shafts. The humble canary would fall dead as a result of increasing toxins particularly carbon monoxide in the air. Being a small creature with rapid respiration and a fast metabolism, toxins accumulate in a bird's system much faster than they would in larger animals. Thus, the miners received advanced warning of an exposure of which they would otherwise be unaware. In other words, the canary had a lower dose response threshhold than humans.

Animals that are prone to showing toxic effects and serve as harbingers of environmental degradation have come to be known as "sentinel species." Cats are susceptible to mercury poisoning, crayfish to water pollution, and bees to air pollution. Even in antiquity, people recognized that when the plague arrived, the rats were the first to die.

The dose also makes the medicine

If the dose makes the poison, it also makes the medicine. For medicines, small doses will have minimal to no effect. Larger doses begin to demonstrate their beneficial effect above a threshold often referred to by clinicians as the "effective" or "therapeutic" dose. Increasing doses from this threshold increases the magnitude of the therapeutic effect up until it approaches toxic levels. This range is known as the therapeutic window.

Acetaminophen, for example, is safely metabolized by liver enzymes within its therapeutic window. Metabolism is a multi-stage process that, at an intermediate stage, generates a toxic metabolite known as N-acetyl-p-benzoquinone imine (NAPQI). If a person has chronic liver disease, or if they take too much of the drug, NAPQI accumulates in their bloodstream and eventually causes permanent liver failure.

Over several centuries, medical researchers have used a process of trial and error to find therapeutic functions of substances long regarded as toxins. The bark, leaves, and seeds of the yew tree (Taxus baccata) have been known to be poisonous for centuries. The witches' brew from Shakespeare's "Macbeth" even cited "slips of yew, silvered in the moon's eclipse" as a main ingredient. Yet, the compound Paclitaxel, derived from the same plant, treats opportunistic infections in AIDS patients as well as a variety of cancers.

For cancer chemotherapy treatments in particular, one must walk a fine line, using the toxicity of a substance to preferentially destroy cancer cells without killing the patient. In this way, tumors are similar to sentinel species. The rapid rate of cellular metabolism that makes cancer cells dangerous also makes them susceptible to toxic exposures as they more quickly incorporate the dose. Cancer treatments then exploit the differential uptake of chemotherapy between healthy and tumor cells to deliver a targeted dose.

Is dose response theory always right?

Paracelsus' doctrine may have been profound, but does that mean it is universally correct? There are at least four cases that complicate dose-response theory as succinctly stated by Paracelsus:

Carcinogens. It is generally believed that there is no "safe" dose for exposure to cancer causing agents and hence, carcinogens are inherently poisonous. Although the likelihood of cancer increases with the exposure dose, a single mutation to a single DNA base pair can be enough to result in cancer.

A cancerous cell, through its uncontrolled growth, escalates its own dose. The seemingly harmless single cancer cell divides to give rise to two such cells, then four, then eight, triggering a geometric expansion towards a cancerous tumor.

Even this line of reasoning however, is disputed by additional nuance. Communities that live at high altitudes are exposed to greater levels of cosmic radiation. Assuming a linear relationship between carcinogen dose (UV radiation) and cancer even at low doses, one would expect these communities to demonstrate higher rates of certain cancers. Yet, no such evidence exists to reveal this expected cancer cluster. This has led to the hypothesis that low-doses of radiation stimulate mechanisms in the body that serve to repair DNA damage. The body's mechanism for culling dead or dangerous cells may effectively limit these micro dose exposures before they give rise to cancerous masses.

Bioaccumulators. In 1958, after noting rising mortality in birds of prey following the widespread spraying of insecticide in New England, conservation biologist Rachel Carson identified the agricultural pesticide DDT as the highly toxic culprit. This finding was published in her influential book Silent Spring. Because raptors were at the top of the food pyramid, the fish they preyed on had in turn eaten smaller fish, which had nibbled on plants contaminated by runoff. At each level of the feeding chain, DDT levels became further concentrated in the organism.

This process, known as "bioaccumulation," arises from the fact that some toxins cannot be metabolized or excreted, and thus become increasingly concentrated up the food chain. Consequently, although there may be a safe dose for a single exposure, bioaccumulation results in the exposure becoming more pronounced over time until a harmful dose is reached. Applying this principle of bioaccumulation to people, particularly those who eat meat and are, therefore, exposed to higher accumulated doses, led to the wide-scale ban of DDT in the US and other high-income countries.

Endocrine Disruptors. Compounds that disrupt the human endocrine system are another example where the apparent simplicity of the dose response curve begins to break down. Endocrine disruptors are chemicals that are similar in structure to the hormones circulating in the human body. Hormone imbalances can have dire health consequences, particularly for the human fetus. Fetal exposure to a microdose of a certain sex hormone can lead to the malformation of sex organs, while the same dose exposure would have zero impact on an adult. Even stranger, the dose response curve for endocrine disruptors may be "non-monotonic" that is, not show a consistent relationship between increasing dose and increasing effect. Small doses may yield significant effects, medium doses may have no effect, and high doses again may show an effect. Any number of puzzling curves have been proposed by toxicologists and researchers in order to explain these phenomena. They all call into question the dose response relationship conceived of by Paracelsus.

Viruses and bacteria. Like cancer, viruses and bacteria have the innate capability to escalate their own dose. A single viral particle that infects a host cell can make millions of copies of itself. This implies that, in theory, there is no lower limit or no truly safe dose. Yet, like cancers, we also do not typically see this play out. Some noroviruses may cause an infection in 50% of people exposed to as low a dose as 20 viral particles. Meanwhile, other viruses and bacteria may be harmless, or in some cases symbiotic, at much higher numbers. The human gut, for example, is a celebration of the therapeutic benefit of many bacteria and even some viruses that work to maintain the body's homeostasis.

What about for the novel coronavirus?

Studies of swab samples demonstrate that New York subways are populated by all manner of viruses and microbes, including everything from anthrax to the plague. And yet exposure of millions of subway riders to these pathogens do not lead to clinical cases of exotic diseases. Similarly, more and more evidence suggests handling a bag of groceries with traces of SARS-CoV-2 virus is not going to make most people sick.

Although in theory there may be no safe dose, as a practical matter, many humans are quite resilient to all kinds of exposures. Recent evidence demonstrates that wearing masks protects wearers by reducing the exposure dose of COVID-19.

Of course, some of us may be the proverbial 'canary in the coal mine' for certain exposures based on our increased susceptibility to the disease. And in the case of many chemicals on the market today, we are all canaries in the coal mine. The experiment, as it were, is ongoing.

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When a little bit of poison is good for you: Inside the theory of dose response - Salon

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A broken heart may conjure up bittersweet stories and love songs but experiencing a traumatic event may actually cause cardiac consequences.

Broken heart syndrome, also known as Takotsubo cardiomyopathy, occurs when someone experiences sudden and acute physical or emotional stress, which can rapidly weaken the heart's left ventricle.

Here's what you need to know about the causes, symptoms, and treatment for broken heart syndrome.

Broken heart syndrome, which was first described in Japan during the 1990s, is a condition where the left ventricle the heart's primary pumping chamber balloons out, while the base of the heart contracts. This may be dangerous because it negatively impacts the heart's ability to pump blood properly.

Conversely, a heart attack happens when blood flow, which brings oxygen to the heart, is restricted or entirely cut off. Although heart attacks and Takotsubo cardiomyopathy are both types of muscle heart failure that can cause similar symptoms, there are some key differences worth noting.

According to Jay Woody, MD, an emergency medicine physician and chief medical officer of Intuitive Health, heart attacks are often caused by blockage from fatty build-up known as plaque in the wall of the arteries which can lead to a clot in the blood vessel that impedes blood flow to the heart muscle. Takotsubo cardiomyopathy, meanwhile, is triggered by a severe emotional or physical response that affects the heart muscle directly.

Broken heart syndrome can set in even if you're otherwise healthy, according to the American Heart Association, which is why it's important to understand the causes and symptoms.

According to Woody, the name "broken heart syndrome" refers to the fact that the condition can be brought on by emotionally traumatic events that negatively impact the physical heart.

He says the most common example of a stressor that can lead to this condition is grief from losing a loved one but notes that intense feelings of fear, anger, surprise, and other emotions can also be a trigger.

Some other events that might cause this condition include:

A 2020 study discovered an uptick in patients diagnosed with Takotsubo cardiomyopathy since the coronavirus outbreak reaching 7.8% compared to 1.7% before the COVID-19 pandemic. Additionally, patients with this condition during the pandemic were found to have a longer hospital stay than those hospitalized pre-pandemic.

Researchers noted that the COVID-19 pandemic has added multiple layers of stress into people's lives not only are many dealing with economic changes, emotional issues, loneliness, and isolation, but they're also grappling with constant concerns about themselves or their loved ones becoming ill. They concluded that this additional stress can have physical effects, as evidenced by the increasing diagnoses of Takotsubo cardiomyopathy.

Broken heart syndrome can also be caused by physical stressors, including:

Even positive events, like walking into a surprise party or winning the lottery, can bring on Takotsubo cardiomyopathy.

"Regardless of the cause of stress, the body's response is similar: to secrete a large amount of the stress hormone adrenaline," says Jennifer Haythe, MD, a critical care cardiologist at Columbia University Center. "In some instances, this can lead to Takotsubo cardiomyopathy, which can mimic a heart attack."

While Takotsubo cardiomyopathy is seen in men and younger women, a 2015 study found that a staggering 89.8% of cases occurred in women between the ages of 58 and 75. The most common triggers were found to be physical (36%), followed by emotional shock (27.7%). Notably, a trigger could not be found in 28.5% of patients. The study also revealed that patients with Takotsubo cardiomyopathy were almost twice as likely as those with acute coronary syndrome (such as heart attack) to have a psychiatric or neurological disorder.

"Patients who have broken heart syndrome may experience chest pain, shortness of breath, and low blood pressure very shortly after an extremely stressful event," says Woody.

According to Johns Hopkins Medicine and the American Heart Association, other symptoms and signs of Takotsubo cardiomyopathy include:

These symptoms may set in anywhere from minutes to hours after someone has gone through a physically or emotionally stressful event.

"Some people describe it as feeling like an elephant is sitting on their chest," says Haythe. "Sweating, jaw pain, left arm pain, nausea, vomiting, lightheadedness, palpitations, and mid-epigastric discomfort are all possible symptoms as well."

If you feel any new symptoms in your chest, or have crushing chest pain or shortness of breath, experts urge you to seek medical attention immediately.

"Heart attacks have similar symptoms as broken heart syndrome, so it's important to get a diagnosis because heart attacks can be fatal," says Woody.

When a patient experiences symptoms similar to broken heart syndrome, medical professionals will typically rely on imaging studies, blood tests, and cardiac biomarkers to observe any potential abnormalities before making an official diagnosis.

Woody says that clinicians often use a cardiac MRI or administer an echocardiogram (cardiac ultrasound) that determines whether or not there is ballooning in the left ventricle, thus signifying Takotsubo cardiomyopathy. They may also use coronary angiograms, a procedure that uses X-ray imaging, to rule out a heart attack.

While it can take up to two to three months to recover after a heart attack, Woody says a person will typically recover from broken heart syndrome within one to six weeks, making a full recovery within one to two months.

A 2015 study revealed that the rate of death for patients with Takotsubo cardiomyopathy was 5.6% per year. While death is rare, heart failure occurs in roughly 20% of patients.

Treatment for broken heart syndrome will depend largely on which symptoms the patient is experiencing, and that, according to Woody, will dictate the severity of the condition. He states that clinicians will often recommend medications like beta-blockers, ACE inhibitors, and diuretics. They may also give aspirin to patients who show plaque buildup in their artery walls.

Beta-blockers and ACE inhibitors can be effective in reducing the effects of stress hormones, thereby helping to prevent a recurrence. Meditation and exercise are also proven to be effective strategies for reducing stress, which may play a role in triggering the disorder.

Some of the complications that can result from broken heart syndrome, according to Woody, include fluid in the lungs, or irregular heartbeat. Obstruction of blood flow from the left ventricle, and rupture of the ventricle wall, are also possible, though rare.

"Symptoms can be treated effectively by medical professionals and are usually not long-lasting," he adds. "Broken heart syndrome can be dangerous, but the condition improves rapidly, which means patients with a naturally strong heart shouldn't experience lasting effects."

Broken heart syndrome can be brought on by both physical and emotional stressors. The most common signs of this condition are chest pain and shortness of breath and you can experience these symptoms regardless of whether or not you have any history of heart disease .

Although broken heart syndrome is short-term and easily treatable, Woody says it's still important to seek medical support to prevent it from causing lasting heart damage, which can lead to other symptoms.

Haythe says that people who have experienced one episode of Takotsubo cardiomyopathy are at risk for a recurrence. However, with quick recognition, exclusion of other causes, and proper treatment, she says this condition has an "excellent prognosis," with most patients making a complete recovery.

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Broken heart syndrome is real here's how physical and emotional stress can affect your heart - Insider - INSIDER

Recommendation and review posted by Bethany Smith